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REVIEW

Fibroblast Growth Factor 15/19: From Basic


Functions to Therapeutic Perspectives

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Emmanuel Somm1 and François R. Jornayvaz1

1
Service of Endocrinology, Diabetes, Hypertension, and Nutrition, Geneva University Hospitals, University of
Geneva Medical School, 1205 Geneva, Switzerland
ORCiD numbers: 0000-0001-9425-3137 (F. R. Jornayvaz).

ABSTRACT Discovered 20 years ago, fibroblast growth factor (FGF)19, and its mouse ortholog FGF15, were the first members of a new
subfamily of FGFs able to act as hormones. During fetal life, FGF15/19 is involved in organogenesis, affecting the development of the ear, eye,
heart, and brain. At adulthood, FGF15/19 is mainly produced by the ileum, acting on the liver to repress hepatic bile acid synthesis and
promote postprandial nutrient partitioning. In rodents, pharmacologic doses of FGF19 induce the same antiobesity and antidiabetic actions
as FGF21, with these metabolic effects being partly mediated by the brain. However, activation of hepatocyte proliferation by FGF19 has long
been a challenge to its therapeutic use. Recently, genetic reengineering of the molecule has resolved this issue. Despite a global overlap in
expression pattern and function, murine FGF15 and human FGF19 exhibit several differences in terms of regulation, molecular structure,
signaling, and biological properties. As most of the knowledge originates from the use of FGF19 in murine models, differences between mice
and humans in the biology of FGF15/19 have to be considered for a successful translation from bench to bedside. This review summarizes the
basic knowledge concerning FGF15/19 in mice and humans, with a special focus on regulation of production, morphogenic properties,
hepatocyte growth, bile acid homeostasis, as well as actions on glucose, lipid, and energy homeostasis. Moreover, implications and
therapeutic perspectives concerning FGF19 in human diseases (including obesity, type 2 diabetes, hepatic steatosis, biliary disorders, and
cancer) are also discussed. (Endocrine Reviews 39: 960 – 989, 2018)

O verweight and obesity, caused by unhealthy


eating and reduced physical activity, are rap-
idly rising worldwide with the consequence of in-
receptors [FGF receptors (FGFRs  to )] (–). The
FGFRs present the same overall structure, with an
extracellular ligand-binding domain (composed of three
creasing the prevalence of type  diabetes (TD) (, ). immunoglobulin-like domains), a transmembrane
Obesity, TD, and related insulin resistance are as- domain, and an intracellular tyrosine kinase domain
sociated with complications involving angiopathies (–). Splice variants for FGFR, FGFR, and FGFR
and nerve damages, but also liver-related diseases (). exhibit differential binding selectivity for FGFs whereas
Nonalcoholic fatty liver disease (NAFLD) is the most no splice variants are known for FGFR (). FGFs also
common hepatic disorder related to obesity and TD bind components of the extracellular matrix such as
(, ). A subset of NAFLD patients develop a state of heparan sulfate and heparan sulfate proteoglycan (,
hepatic inflammation [nonalcoholic steatohepatitis ). This interaction increases the stability and affinity
(NASH)], which can progress to fibrosis, cirrhosis, and of FGFs for FGFRs and limits their diffusion within the
ultimately result in hepatocellular carcinoma (HCC) local environment (, ). In fact, FGFs classically
ISSN Print: 0163-769X (). Apart from lifestyle changes, including weight loss signal through a paracrine manner, especially between
ISSN Online: 1945-7189 and physical activity, there is currently no efficient epithelium and mesenchyme (). FGFs and FGFRs
Printed: in USA long-term drug to improve and/or avoid development present highly specific expression patterns, determining
Copyright © 2018 selectivity of their sites of action (). Moreover, the
and progression of obesity, TD, and NAFLD.
Endocrine Society
Fibroblast growth factors (FGFs) form a large expression of FGFs and FGFRs is temporally regulated.
Received: 27 April 2018
Accepted: 10 July 2018 family of . signaling molecules with pleiotropic Some FGFs are mainly expressed during develop-
First Published Online: functions in different areas of biology (). FGFs bind ment whereas others are more involved in adult
14 August 2018 and signal through four membrane tyrosine kinase tissues homeostasis ().

960 https://academic.oup.com/edrv doi: 10.1210/er.2018-00134


REVIEW

ESSENTIAL POINTS
· Human fibroblast growth factor (FGF)19 and its mouse ortholog FGF15 are gut-derived circulating hormones
(enterokines) that repress hepatic bile acid synthesis and change their composition through the FGF receptor 4 and the
coreceptor b-Klotho complex
· FGF15/19 is involved in the early development of ear, eye, heart, and brain during organogenesis, as well as in muscle
growth at adulthood
· Mouse FGF15 and human FGF19 exhibit differences in terms of regulation, molecular structure, signaling, and biological
actions, implying a careful interpretation of data originating from the use of FGF19 in murine models
··

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In rodents, pharmacologic doses of FGF19 induce similar antiobesity and antidiabetic effects as does FGF21
Some of the metabolic effects of FGF15/19 appear to be mediated by the brain
· Stimulation of hepatocyte proliferation represents the main risk to use of FGF19 as a drug, but this effect can be overcome
by genetic reengineering of the molecule
· In addition to obesity and type 2 diabetes, FGF19 can also be a therapeutic target in type 1 diabetes, in diseases associated
with bile acid overproduction, and in hepatocellular carcinoma

For many years, investigations concerning FGFs FGF, mainly produced by the liver during metabolic
mainly focused on proliferation, migration, and dif- stress, regulates numerous metabolic processes, in-
ferentiation processes, in particular in the field of cluding glucose and lipid homeostasis. Thus, it rep-
developmental biology (). The recent discovery of a resents an interesting candidate for treatment of
new subgroup of FGFs, namely endocrine FGFs, has obesity and TD ().
stimulated medical research in the field. Although The present review will deal with FGF and its
FGF/, FGF, and FGF, the three endocrine mouse ortholog FGF, with particular focus on the
FGFs, present different structures and functions, they regulation of its production, its physiological and
all bind poorly to heparin and derivatives (). This pharmacological actions, as well as its involvement in
allows these FGFs to diffuse beyond the interstitial human diseases and potential use in the treatment of
space to reach the bloodstream and act far from their metabolic and gastrointestinal diseases. As much
tissue of origin, as classical endocrine hormones (). of the basic knowledge in the field of FGF/ bi-
In this way, FGF derived from bone acts on the ology comes from murine studies, species differences
kidney to regulate phosphate reabsorption and vita- in the functions of FGF/ between rodents and
min D production, representing an important endo- humans will also be highlighted in a translational
crine loop in the control of mineral homeostasis (). perspective.

Molecular Biology of FGF15/19 human and mouse FGF orthologs (), explaining
their divergent names. However, based on the evo-
FGF15/19 gene and protein lutionary conservation of the CCND-ORAOV-
Murine FGF was initially identified as a downstream FGF-FGF locus from zebrafish to humans, it
target of the chimeric oncoprotein EA-Pbx in the was concluded that the human FGF gene was the
NIHT cell line (). The FGF gene is located on ortholog of the murine FGF gene ().
chromosome  and consists of  exons. The FGF
protein, composed of  amino acids, is the most FGF15/19 structure and affinity for
divergent among the known FGF family members receptors/coreceptors
(). Subsequent screening of expressed sequence tags Compared with other FGFs, the key heparin-binding
led to the discovery of FGF cDNA from human sites of FGF have radically different conformations
neuroepithelial cells showing sequence homology with and charge patterns (, ). In particular, the con-
the corresponding region of mouse FGF (). The formation of the heparin-binding region between
chromosomal location of FGF was found to be b-strands  and  in FGF diverges completely
chromosome q., a genetic region associated with from the analog region of paracrine-acting FGFs ().
an osteoporosis-pseudoglioma syndrome (). The A cleft between this region and the b–b loop (the
whole FGF coding region revealed a complete other heparin-binding region) precludes direct in-
protein sequence of  amino acids sharing % teraction between FGF and heparin/heparan sul-
similarity with mouse FGF (). The homology fate (), reducing the heparin-binding affinity and
between the human FGF and mouse FGF was facilitating the endocrine function (). These con-
significantly less than that observed between most formational predictions are confirmed by in vitro

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experiments showing little or no affinity of FGF for signal through FGFRs associated with lactase-like
heparan sulfate/heparin (). Klotho (). However, the biological relevance of
The coreceptor b-Klotho (KLB) has emerged as a this signaling complex remains unknown.
compensatory mechanism for the poor ability of
heparin/heparan sulfate to promote binding of FGF FGF15/19 intracellular signaling pathways
to cognate receptors (). KLB is a single-pass FGFs mediate their cellular responses by the binding
membrane protein consisting of two internal repeats and activation of FGFR– (, ). FGF/FGFR in-
with homology to family  glycosidases (). Crystal teraction induces receptor dimerization, activation,
structures of KLB extracellular regions reveal that its and autophosphorylation of multiple tyrosine residues
glycosidase substrate-binding domain has evolved in the cytoplasmic domain (, , ).

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to recognize a sugar-mimicking Ser-Pro-Ser motif Most of the knowledge concerning intracellular
present in FGF (). Use of chimeric proteins de- events mediating FGF/ actions comes from in
veloped from members of the endocrine FGF sub- vitro work involving various cell lines. In transfected
family and Klotho family identified the C-terminal tail HEK, L, T-L, and Caco- cell lines, FGF
of FGF as being required for KLB recognition and induces phosphorylation of FGFR substrate a
signaling (). Interestingly, FGF possesses a unique (FRSa) and ERK/ (, , , ). FGF also
unpaired cysteine (Cys) that permits dimerization activates the mammalian target of rapamycin complex
of monomers and is absent in FGF and all other –pSK and ERK–pRSK pathways independently
endocrine FGFs (). This structural feature can ex- to regulate S in an additive manner in hepatoma cells
plain functional divergence from the human FGF. and in T-L adipocytes (). FGF signals to
FGF exhibits a high specificity for FGFR mammalian target of rapamycin complex  through
binding (). Unique sequences in both FGF and Ras-like protein to regulate gene expression in HepG
FGFR are key to the formation of the complex, cells (). FGF signaling through FGFR phos-
offering a conformational explanation for this unusual phorylates the inhibitor of nuclear factor kB ki-
selective affinity (). Different amino acids at both the nase subunit b in HEK and DU cell lines,
N and C termini of FGF contribute to full FGFR inhibiting inflammation through the downregulation
activation (). Nevertheless, amino acid residues  to of nuclear factor kB (). Beyond phosphorylation
 of FGF are sufficient to confer FGFR activation cascades, FGF stimulates the transcription of early
to other endocrine FGFs (). response genes (c-Fos, JunB, and c-Jun) in HepG
Whether FGF/ can directly interact with and HepB cell lines (). FGF also increases
FGFR in the absence of KLB remains controversial small heterodimer partner (SHP) protein stability by
and possibly concentration-dependent (–). inhibiting its ubiquitination and proteasomal degra-
Whereas FGFR is only activated by FGF among dation (). Finally, in primary cultures, FGF acti-
endocrine FGFs, FGF can also bind and signal vates the c-Jun N-terminal kinase pathway in human
through other FGFRs. In fact, FGF binds FGFR hepatocytes (), induces phosphorylation of forkhead
with comparable affinity to FGFR in the presence of box O (FoxO) in mouse hepatocytes (), and in-
KLB (). Furthermore, FGF can signal through creases the phosphorylation of signal transducer and
FGFR– bound by KLB (–), especially at a activator of transcription  (STAT) in rat hepatocytes
supraphysiological concentration (). Additionally, each ().
FGFR isoform (originating from splice variants) has a Intracellular signaling downstream of FGF/
different affinity for KLB. FGFRc and FGFR bind KLB has also been investigated in vivo. Acute FGF ad-
more potently than FGFRc or FGFRc whereas type ministration induces phosphorylation of ERK/ (,
b isoforms of FGFRs fail to interact with KLB (). As a ) and c-Fos expression () in mouse liver. The
consequence, FGFR isoform composition also impacts phosphorylation of ERK/, as well as several other
FGF/ binding to KLB–FGFR complexes. signaling events triggered by FGF/, such as the
In contrast to the wide distribution of FGFRs in the activation of ribosomal S kinase (pRSK), SHP
body, the pattern of Klotho protein expression is more upregulation, and protein kinase C phosphorylation,
limited () and defines the main tissue targets of appears dependent on the presence of the nonreceptor
endocrine FGFs. In mice, the FGFR gene is highly tyrosine phosphatase with two Src homology  do-
expressed in kidney, liver, lung, and adrenal, whereas mains in mouse liver (). Src homology  forms a
KLB expression is high in enterohepatic tissues (liver, complex with FRSa and Gab upon FGF stimu-
gallbladder, colon, and pancreas) and white adipose lation (). Chronic FGF overexpression increases
tissue/brown adipose tissue (BAT) (). The liver is the the hepatic phosphorylation of both FoxO and
only organ in which FGFR and KLB are abundantly protein kinase B (also known as Akt) (). FGF also
coexpressed (, , ) and is in consequence the increases the phosphorylation of eukaryotic trans-
main target tissue of FGF/. In line with this lation initiation factor B, eukaryotic translation ini-
concept, early response genes are only induced in the tiation factor E, ribosomal protein S, FRSa, ERK,
liver of FGF-injected mice (). FGF can also pRSK, glycogen synthase kinase (GSK)a, and

962 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

GSKb in mouse liver (). Importantly, FGF pharyngeal pouches, and the tail bud (). FGF
equally induces hepatic STAT phosphorylation expression first appears at embryonic day (E). in the
(–). Administration of FGF to mice also acti- mouse neuroectoderm before exhibiting a highly
vates the phosphorylation of the ERK/ signaling dynamic expression pattern during brain development
pathway in extrahepatic tissues, including adipose (). In the diencephalon, strong FGF expression is
tissue (), the hypothalamus (), and the ileum (). initially seen in the dorsal thalamus before the ex-
Note that concentrations of FGF/ used in tension to the ventral thalamus (). In the mesen-
these in vitro and in vivo studies can be several orders cephalon, FGF is first expressed caudally before
of magnitude higher than the maximal circulating being predominantly observed rostrally at later de-
values observed in animals or humans, even post- velopmental stages (). In the telencephalon, FGF

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prandially or following pharmacologic/nutritional is detected in the olfactory bulb region (). FGF
stimulation. Although higher levels of FGF/ expression is also detected in the inner cell layer of the
can be present in the portal circulation compared optic cup, in the rostral hindbrain regions (rhombo-
with the systemic blood circulation, one should be meres  and ), in the caudal hindbrain, in the cervical
cautious concerning direct translation of the basic spinal cord, and in the terminal rostral hypothalamus
signaling studies to human physiology. The main (, ). In contrast, during adulthood, FGF globally
intracellular signaling pathways mediating FGF/ disappears from the central nervous system (), al-
actions in hepatocytes are illustrated in Fig. . though recent work found FGF expression in
specific neurons of the dorsomedial hypothalamus and
the perifornical area (). Instead, the FGF gene is
Production of FGF15/19 highly expressed in the ileum (distal part of the in-
testine) and also detected in the jejunum and duo-
Tissue specificity of FGF15/19 expression denum (more proximal intestine segment) of adult
During murine development, the FGF gene is mice (, ). At the cellular level, FGF expression is
predominantly expressed in the nervous system, the detected in the enterocytes of the villus epithelium

Figure 1. Intracellular signaling pathways triggered by FGF15/19 in the hepatocyte. FGF15/19 binds to tyrosine kinase receptor FGFR4
associated to the coreceptor KLB. After recruitment of docking and adapter proteins, FGFR4 activation regulates the activity of several
protein kinases and transcription factors involved in different biological processes. Green arrows represent activation/induction; red
lines represent inhibition/repression. CREB, cAMP regulatory element–binding protein; eIF4B, eukaryotic translation initiation factor
4B; eIF4E, eukaryotic translation initiation factor 4E; Grb2, growth factor receptor–bound protein 2; JNK, c-Jun N-terminal kinase; Mnk1,
MAPK-interacting protein kinase 1; mTORC1, mammalian target of rapamycin complex 1; Nrf2, nuclear factor erythroid 2–related
factor 2; PGC-1a, peroxisome proliferator-activated receptor-g coactivator 1a; PGC-1b, peroxisome proliferator-activated receptor-g
coactivator 1b; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; Ral, Ras-like; rpS6, ribosomal protein S6; RSK, p90RSK
ribosomal S6 kinase; Shp2, nonreceptor tyrosine phosphatase with two Src homology 2 domains. [© 2018 Illustration Presentation
ENDOCRINE SOCIETY].

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with highest expression in the intervillus regions (). human circulation (median  pg/mL, variation
Little or no FGF is observed in the ileal crypts or .-fold) (). Circulating FGF levels appear to be
lamina propria (). Of note, FGF expression in the unrelated to age or sex in healthy humans (, ).
ileum is weaker during gestation and lactation in mice However, other studies show that circulating FGF
and rats (–). In the pig intestine, expression of surges .-fold in early infancy from infra-adult to
FGF begins soon after birth but achieves maximal supra-adult concentrations (). However, this in-
expression in the ileum during adulthood (). duction is reduced in small-for-gestational-age infants
In the human fetus, in situ hybridization and RT- (). Surprisingly, centenarians also exhibit increased
PCR analyses reveal FGF expression in brain, skin, FGF levels, independently associated with their
cartilage, inner retina, small intestine, kidney, as well as successful aging (). As FGF is mainly produced by

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placental villi and the umbilical cord (). FGF is the ileum, a primary delivery is expected in the portal
also expressed in human embryonic stem cells, and circulation. In this way, portal levels of FGF are
expression levels correlate positively with the un- higher than arterial levels (). A net release of FGF
differentiated state (). In adulthood, FGF ex- by the portal-drained viscera can be calculated under
pression is detected in biopsies from human ileum, but fasted steady-state conditions, although no significant
not in biopsies from human colon (). FGF is not flux of FGF can be measured across the liver ().
detected basally in human liver. Nevertheless, hepatic This suggests that most intestine-derived FGF binds
expression can be induced during cholestasis or cir- to hepatocytes or the hepatic extracellular matrix
rhosis (, ). Nonparenchymal cells, notably chol- during the first pass through the liver and does not
angiocytes (the cells lining the bile duct), largely substantially reach peripheral tissues, at least at the
contribute to FGF expression in the cholestatic liver same concentration. Surprisingly, human bile con-
(). Additionally, stimulated human hepatocytes also tains - to -fold more FGF than does the
exhibit FGF induction in vitro (). Finally, FGF is systemic circulation (, ). The likely sources of
also expressed in human gallbladder epithelial cells biliary FGF are the gallbladder and the extrahepatic
(, ). This expression appears even more abundant bile duct, both exhibiting high expression levels of
than in the ileum (, ). FGF (, ).
In summary, whereas FGF expression is re- In the gallbladder epithelium, FGF protein is
stricted to the distal part of the intestine in adult mice, present in cytoplasmic granules similar to secretory
gallbladder and cholestatic liver also express FGF in vesicles (). The role of this exocrine secretion is
humans. A comparison of FGF and FGF ex- unknown and the impact of gallbladder-derived
pression patterns in mice and humans is illustrated in FGF on the circulating pool remains elusive. In
Fig. . fact, the lowering effect of bile acid (BA) sequestrants
on serum FGF levels rather suggests a limited
FGF15/19 secretion contribution of tissues other than the ileum ().
FGF accumulates in a time-dependent manner in
the media of cells infected with an FGF-expressing Regulation of FGF15/19 production
adenovirus, revealing the secretion of the protein ().
However, FGF is a weak antigen, and detection of Molecular regulators
FGF in the blood has long been problematic, As with other endocrine FGFs, FGF/ is tran-
questioning its real endocrine action (). Initially, scriptionally regulated by nuclear receptors. Farnesoid
FGF was not detected in the rat portal circulation X receptor (FXR) is the classical nuclear receptor for
using mesenteric perfusion, suggesting a low level of BAs (, ). FGF is the most induced gene in
production/secretion or a high lability of the protein human hepatocytes treated with the FXR synthetic
(). Moreover, FGF protein levels in the portal agonist GW or the BA chenodeoxycholic acid
blood do not match with the marked increase in (CDCA) (). The FGF gene contains functional
FGF expression observed in the stimulated ileum FXR-responsive elements within the second intron
(). Nevertheless, an assay by stable isotope stan- () and in the promoter region (). Analogously, rat
dards and capture by an antipeptide antibodies and mouse FGF genes contain FXR-responsive el-
assay, combining immunoenrichment with mass spec- ements in intron  (), and FGF gene expression is
trometry, has overcome this issue (). This new dosage dramatically increased in the intestine following
technique shows that () FGF circulates in plasma () GW administration (, ). Intestine-specific
in a regulated manner, () at concentrations that are FXR-deficient mice show a strong downregulation
known to activate its receptor, and () in strong corre- of FGF expression in the ileum (), whereas
lation with ileal gene expression (). transgenic mice expressing a constitutively active FXR
Compared with FGF, immunological methods in the intestine present an increased FGF expression
for detection (RIA- or ELISA-based assays) of FGF in this tissue (). The FXR-mediated transcriptional
are more reliable, which has allowed the observation activation of FGF is negatively regulated by sterol
of a wide interindividual variation of concentration in regulatory element binding protein (SREBP)- in

964 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

Figure 2. Comparison of
main anatomical sites of
FGF15 expression in mice
and FGF19 expression in
humans. Level of FGF15/19
expression is indicated by
font/image size. Note that
liver cholangiocyte FGF19
expression was found in
humans with cholestatic
conditions. [© 2018

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Illustration Presentation
ENDOCRINE SOCIETY].

human intestinal cells (). In turn, FGF increases FXR gene expression) and direct binding to a con-
functional interaction between SHP and SREBP-, sensus GATA regulatory element in intron  of the
leading to repression of SREBP- target genes (). FGF gene ().
Pregnane X receptor (PXR) is another nuclear In addition to transcriptional regulation, FGF
receptor whose primary function is to sense exogenous concentration seems to be controlled at the post-
toxic substances, leading to the upregulation of de- transcriptional level. Indeed, the protein Diet
toxification proteins (). Highly hydrophobic BA, colocalizes and interacts with FGF to enhance its
such as lithocholic acid (LCA), can also bind PXR (). production levels via both transcriptional and post-
Overexpression of PXR and stimulation with its ligand transcriptional mechanisms (). Diet-deficient mice
rifampicin lead to a significant activation of the have reduced ileal FGF levels (). The regulation of
proximal FGF promoter region in a human ade- FGF/ production in mice and humans, including
nocarcinoma cell line (). In contrast, PXR appears to transcriptional regulators involved, is summarized in
regulate negatively FGF expression in mice (). The Fig. .
promoter region of FGF also possesses a functional In addition to the direct regulation of its pro-
amino acid response element, responsible for en- duction, the action of FGF/ can be modulated
hancing transcription through activating transcription through the tuning of its coreceptor KLB. In this way,
factor  in response to endoplasmic reticulum stress FXR activation also primes the liver for FGF/
(). Induction of FGF is also observed after si- signaling through hepatic induction of KLB expression
lencing release through blockade of cytosine guanine (). In contrast, miRNA-a inhibits KLB expression
dinucleotide–binding domain proteins in HeLa cells and attenuates hepatic responses to FGF (). In the
(). Furthermore, FGF gene expression can be same way, IL-b specifically inhibits KLB expression
induced in colonic myofibroblasts through inhibition and FGF signaling in the liver () whereas TNF-a
of miR- by carbon monoxide treatment (). represses KLB expression in adipose cells (). Fi-
The FGF gene can also be repressed by tran- nally, as KLB is the obligate coreceptor for both FGF
scription factors. Krüppel-like factor  (KLF) binds and FGF/, FGF overexpression antagonizes
the FGF promoter at multiple consensus binding FGF/ binding to the KLB/FGFR receptor complex
sites and represses FGF expression independently of in mouse liver ().
BAs (). Overexpression of KLF in primary small
intestinal epithelial mouse cells potently represses BAs
FGF gene expression, whereas knockdown of KLF As endogenous ligands for FXR, BAs are the pro-
induces FGF expression (). The transcription totypical inducers of FGF/. As a consequence,
factor GATA represses FGF transcription within the modification of their concentrations and/or
the proximal intestine and limits its expression to the composition in the small intestine directly impacts
ileum (). This inhibition occurs through both in- FGF/ production. Four days of diet containing
direct mechanisms (modification of BA uptake and cholic acid (CA) increases FGF expression in the

doi: 10.1210/er.2018-00134 https://academic.oup.com/edrv 965


REVIEW

mouse ileum (). In contrast, administration of BA for the apical sodium-dependent BA transporter
sequestrants (resins binding BA and preventing their (, ).
reabsorption from the intestine) causes a steep de- In humans, both feeding () and intraduodenal
crease in ileal FGF gene expression in mice (, infusion () of CDCA increase circulating FGF
). Of note, BA species have different impacts on levels. Conversely, administration of UDCA to obese
the expression of FGF. Oral supplementation with patients for  weeks reduces their circulating FGF
CA or deoxycholic acid (DCA) increases the ileal levels (). Basal circulating FGF levels are also
expression of FGF at lower doses and to a higher reduced following treatment with BA sequestrants in
extent than CDCA or LCA in mice (). Conversely, patients (, –). After cessation of treatment,
oral supplementation with ursodeoxycholic acid FGF displays rebound increases above baseline

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(UDCA) does not induce FGF expression in the levels (). In contrast, BA sequestrants in colonic-
ileum (). Coadministration of tauro (T)–b- release pellets fail to regulate FGF levels (). The
muricholic acid (bMCA) attenuates T-CA–induced selective ileal BA transporter inhibitor A de-
FGF expression in germ-free mice (), in line creases circulating FGF levels by % as soon as
with the antagonist action of T-bMCA on FXR  hours after administration (). In human ileal
evidenced in this study. Nevertheless, the ability of explants, FGF expression is strongly induced by
orally administered BA to stimulate FGF in mice CDCA, glyco-CDCA, and CA, but DCA and LCA are
intestine only partially matches their agonistic significantly less potent (). In human primary he-
activity on FXR (CDCA . DCA . LCA  CA) patocytes, all BAs increase FGF gene expression,
(), possibly due to chemical conversion of the with the rank orders of FGF induction being CDCA
ingested BAs (as for example the bioconversion of ' CA . DCA ' LCA . UDCA (, ). The
CDCA into MCA in rodents). Moreover, beyond semisynthetic BA analog obeticholic acid also in-
the specific ability of BA to activate the FXR re- creases FGF secretion through FXR activation in
ceptor, transepithelial transport of BA is also a key human primary hepatocytes (, ) and in Caco-
step in the regulation of FGF/ production. cells in which it is more potent than glyco-CDCA
Inhibiting apical vs basolateral BA transport in the ().
ileum results in opposite regulation of FGF. In
fact, FGF expression is strongly elevated in the Gut microbiota/antibiotics
ileum of mice deficient in the basolateral BA The crosstalk between microbiota and the intestine
transporter organic solute transporter a (), wall, as well as the ability of gut microbiota to
whereas it is reduced in the ileum of mice deficient transform BA through various chemical processes

Figure 3. Regulation of FGF15/19 production in mice and humans. Stimulatory effects are indicated by plus signs (+), inhibitory effects
by minus signs (2). Data were derived from clinical observations/studies and cell cultures in humans (h) and experimental studies and
cell cultures in mice (m). ASBT, apical sodium-dependent BA transporter; KLF15, Krüppel-like factor 15; RAR, retinoic acid receptor;
VDR, vitamin D receptor. [© 2018 Illustration Presentation ENDOCRINE SOCIETY].

966 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

(such as deconjugation and dehydroxylation), suggest reduction in the intestinal expression of FGF, but
that the gut microbiota can be a key player in the surprisingly, this occurs independently of any damage
regulation of FGF/. This was first proven by to the ileal enterocyte layer ().
the use of antibiotics. Administration of nonab-
sorbable antibiotic cocktails (ampicillin or bacitracin/ Macronutrients and micronutrients
streptomycin/neomycin) significantly decreases FGF Both chronic imbalance of diet composition in mice
expression in mouse ileum (, ), in association with and acute administration of a single type of macro-
dampening of FXR signaling (). A compensatory nutrient in humans impact FGF/ production.
increase in BA import and FGF expression can be Consumption of an HFD stimulates FGF ex-
observed in regions of the proximal small intestine in pression in mouse ileum (). Palmitic acid induces

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parallel with the decrease observed in the ileum following FGF gene expression in mouse ileum and also in-
antibiotic exposure (). Antibiotic-mediated repression duces FGF expression in human hepatocytes ().
of the FGF gene can be prevented by supplementation Although the ingestion of lipids triggers BA release, the
with T-DCA or CA, but not with T-CA or bMCA (, FGF secretion profile during a lipid tolerance test in
). This suggests that stimulation of FGF gene ex- humans remains uncertain (, ).
pression by gut microbiota is due to its ability to A sucrose-rich diet also induces the expression of
deconjugate T-CA into CA, which then adequately ac- FGF in mouse ileum (). In healthy humans, the
tivates FXR signaling (). In line with this concept, FXR ingestion of carbohydrates induces the most rapid and
and FGF levels are higher in the ileum of conven- highest increase in circulating FGF levels compared
tionally raised mice compared with germ-free mice (). with other macronutrients (). Because carbohy-
In turn, colonization of germ-free mice with mouse drate intake exerts little effect on global circulating BA
microbiota induces expression of FGF in their ileum levels, the underlying mechanism could be related
whereas the induction is delayed after colonization with either to a modification in BA composition (impacting
a human microbiota (). The microbiota-induced FXR activation) or another pathway independent of
upregulation of FGF in the ileum is abolished in the BA–FXR axis (). Nevertheless, neither glucose
FXR-deficient mice (). nor insulin seems to mediate the rise in FGF se-
Moderate changes in gut microbiota through the cretion because their postprandial levels were not
administration of prebiotics or probiotics impact less associated with the FGF response (). The FGF
consistently FGF expression in mice. Administra- increment after oral glucose loading is positively
tion of the antioxidant tempol reduces the proportion associated with age and negatively associated with
of Lactobacillus (and its important bile salt hydrolase abnormal glucose regulation (). The drop in cir-
activity responsible for the deconjugation process). culating CDCA levels in patients with isolated-
This leads to the accumulation of intestinal T-bMCA impaired fasting glucose could explain their lower
(an FXR antagonist) and reduction of FGF ex- FGF secretion during a glucose tolerance test ().
pression in mouse intestine (), corroborating FGF expression is not changed in the ileum of
studies using antibiotics. In contrast, supplementation mice fed a leucine-deficient diet for  week (). Ileal
with the VSL# probiotic (comprising several strains FGF expression is increased in rats fed soy proteins
of Lactobacillus and Bifidobacterium) shifts gut compared with rats fed casein (). However, the
microbiota and enhances BA deconjugation but re- addition of cholesterol to the soy protein diet is
presses ileal FGF expression (). Resveratrol ad- sufficient to repress FGF production (). In
ministration, which enriches gut microbiota in healthy humans, protein intake induces a modest and
Lactobacillus and Bifidobacterium, also decreases ileal delayed elevation of FGF when compared with
FGF production (). Chronic ethanol treatment, levels observed after carbohydrate ingestion ().
associated with an overrepresentation of bacteria In a -month dose-response study evaluating
deconjugating BA and thus an increased amount of undernutrition, only the most severe caloric restriction
unconjugated BA in the intestine, dampens FGF (% reduction of daily food intake) tends to increase
secretion (). The supplementation with Lactoba- FGF gene expression in the mouse ileum (). This
cillus rhamnosus in high-fat diet (HFD)–fed mice does upregulation appears to be caused by the increased
not induce any change in intestinal FGF expression intestinal BA content (in particular more hydrophobic
(). Taken together, these results suggest that the BAs) (). In humans, few data regarding the impact
presence of gut microbiota is required for physio- of caloric restriction are available, but higher FGF
logical BA deconjugation allowing a normal FGF levels are reported in children suffering from severe
expression. Nevertheless, enrichment of gut micro- acute malnutrition ().
biota with species harboring a high BA deconjugating Fat-soluble vitamins stimulate both FGF and
activity does not allow positive regulation of FGF. FGF transcription, but species differences are ob-
Finally, pathogenic bacteria can also regulate FGF. served in terms of nuclear receptors involved in this
Indeed, infection with Salmonella or intravenous ad- process. In fact, receptors for vitamin A and D induce
ministration of Listeria both trigger a significant the expression of the FGF gene through distinct

doi: 10.1210/er.2018-00134 https://academic.oup.com/edrv 967


REVIEW

cis-acting response elements in the promoter and enterocytes (). In contrast, dextran sulfate sodium–
intron of the FGF gene. Transactivation of both treated mice with ileum-sparing colitis show higher
response elements appears to be required to maintain circulating FGF levels (). IL-–deficient mice
basal FGF expression levels in vivo (). In mice, with ileitis have a trend toward decreased circulating
induction of FGF by vitamin D is mediated through FGF levels compared with controls (). Mice
vitamin D receptor independently of FXR, whereas the suffering from colitis-associated cancer, exhibiting a
induction of FGF by vitamin A is mediated through concomitant decrease in FXR agonists and antagonists
the retinoid X receptor/FXR heterodimer, indepen- BAs in the ileum, have repressed FGF expression in
dently of BA (). In human intestinal cell lines, the ileum (). Mice with acute cerulein-induced
vitamin A derivatives induce FGF transcription pancreatitis also exhibit a reduction of ileal FGF

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(). In contrast to mouse FGF, this direct regu- expression ().
lation is FXR-independent and mediated by retinoid X Liver disease models also interfere with normal
receptor/retinoic acid receptor heterodimer acting FGF expression in the gut. Mice with chemically
on a DR- element (). induced cholestatic liver injury exhibit a reduction of
Classically known to stimulate FGF production, FGF expression in the ileum (). In contrast,
the availability of inorganic phosphate (Pi) inversely hypercholanemic organic anion–transporting poly-
impacts FGF production. In fact, dietary Pi re- peptide-deficient mice and sodium taurocholate
striction upregulates FGF expression in mouse il- cotransporting polypeptide–deficient mice present
eum, but not in vitamin D receptor–deficient mice increased FGF expression, in line with observations
(). Conversely, high Pi–fed mice have significantly in mice treated with a specific sodium taurocholate
lower transcript levels of FGF in the ileum (). cotransporting polypeptide inhibitor (). Mice
overexpressing the bile salt export pump (ABCB)
Circadian rhythm also show strongly elevated FGF expression levels in
In mice, circadian analyses reveal the highest FGF the ileum (). Mice with hepatocyte-specific ex-
expression in the ileum at the end of the dark phase pression of a dominant stable form of b-catenin
(feeding period for rodents) and the lowest FGF exhibit severe cholestasis and high ileal FGF ex-
expression at the end of the light phase (resting period pression levels ().
for rodents) (, ). A strong correlation between ileal
FGF expression and circulating FGF levels was Surgical procedures
observed across the day in mice (). Maximal ileal Bariatric surgeries, such as Roux-en-Y gastric bypass
expression and circulating FGF levels were observed (RYGB), vertical sleeve gastrectomy, and gastric
in the middle of the light phase in this study (). The banding, cause substantial weight loss and are now
transcription factor KLF is directly involved in the popular treatments for obesity (–). Beyond the
circadian control of FGF. In fact, KLF-deficient decrease in body weight, these surgical procedures
mice lose the daily pattern of FGF production with induce substantive metabolic changes, notably af-
increased levels at multiple time points across a fecting FGF/ levels.
-hour cycle (). Gastric banding consists of the placement of a
The circadian pattern of FGF production driven silicone ring around the stomach to create a small
by food consumption in mice is quite analogous to upper gastric pouch at the bottom of the esophagus
that observed for FGF in humans. In fact, circulating (–). An initial report showed no significant
FGF levels exhibit a pronounced diurnal rhythm in change for basal circulating FGF levels after gastric
humans, with peaks occurring  to  minutes after banding compared with preoperative values (),
the postprandial rise in serum BA (). Moreover, the whereas more recent studies report a decrease ()
rhythmicity of circulating FGF is abolished upon or a continuous increase (). Postprandial circu-
fasting () and altered following cholecystectomy lating FGF concentration increases after laparo-
(), highlighting regulation by the transintestinal BA scopic adjustable gastric banding ().
flux. In the RYGB, a small gastric pouch is created,
draining alimentary bolus into the jejunum (alimen-
Intestinal/hepatic disease models tary limb), which causes nutrients to bypass the py-
The expression of FGF has also been investigated in lorus and duodenum (). Early and late observations
the intestine of various mouse models mimicking after RYGB surgery reveal that fasting circulating levels
human diseases of the digestive system. Ileal FGF of FGF are elevated compared with preoperative
expression is decreased in mice with dextran sul- values (, –). Circulating FGF levels also
fate sodium–induced colitis (). This change is increase after biliopancreatic diversion () and after
due to overactivation of the intestinal peroxisome implantation of a duodenojejunal bypass liner ex-
proliferator-activated receptor (PPAR)a– uridine cluding the duodenum and proximal jejunum from
9-diphosphate-glucuronosyltransferases axis, which contact with ingested food (). The rise in FGF
promotes the metabolic elimination of BAs in seems directly related to the surgery because no change

968 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

is observed in subjects who achieve similar im- homozygous mice can survive (). In contrast,
provements in glycemic control () or weight loss under a SvJ background, FGF KO mice are
() by conventional dietary treatment. The post- viable and fertile ().
prandial peak of FGF also occurs earlier and
reaches a higher value in RYGB patients (, ). Otic development
Nevertheless, other studies show no change in fasting From the earliest stages of development, the FGF
FGF levels acutely or until  year after RYGB (), gene is expressed in anatomic regions involved in
or report nonsignificant trends of increased FGF inner ear development in the chick (). As a me-
levels from presurgery to  years postsurgery (). diator of the mesodermal signal, FGF synergistically
One possibility is that surgery can change FGF levels interacts with Wnt-c (mediating neural signals) to

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in only some patient subsets. In fact, no change in initiate inner ear development (). The FGF gene
circulating FGF levels is detected in RYGB patients is induced in the mesoderm by FGF originating from
exhibiting normal preoperative glucose tolerance, the endoderm, and, in turn, FGF stimulates neural
whereas low levels of FGF observed in diabetic ectoderm to express signals promoting the otic pla-
patients gradually increase after RYGB surgery (). code (). FGF signaling is required to initiate a
Sleeve gastrectomy consists of the creation of a proliferative progenitor region that is a precursor of
long, thin, longitudinal gastric pouch or sleeve, re- both the inner ear and the neurogenic epibranchial
ducing the volume of the stomach by ~% to %, but placodes ().
leaving the pylorus intact (). Fasting and post- Mouse FGF KO embryos do not have otic ab-
prandial FGF levels increase after sleeve gastrectomy normalities at E. to E. (). Unlike FGF,
(–), possibly in line with changes in BA FGF is not expressed in the mesoderm underlying
composition observed after this surgical procedure the presumptive otic placode, but is expressed in the
(). Circulating FGF also increases after laparo- adjacent neurectoderm (). This suggests that
scopic greater curvature plication (). during otic induction, FGF signals in either an
Surgical procedures also regulate FGF in rodents. autocrine fashion to the mesoderm or a paracrine
In mice, ileocecal resection leads to the upregulation of fashion to the neurectoderm, whereas FGF signals in “Beyond the decrease in body
FGF expression in the ascending colon, but this an autocrine fashion to the neurectoderm (). weight, these surgical
compensation is absent in germ-free mice and in FXR- procedures induce substantial
deficient mice (). After bile flow diversion through Eye development changes, notably affecting
gallbladder anastomosis to the ileum, FGF gene In the developing chick, FGF is expressed in the FGF15/19 levels.”
expression is repressed more than twofold in the retina, optic vesicle, lens primordia, retinal horizontal
ileum, despite a massive increase in circulating BAs cells (), and, more acutely, in the postmitotic
(mainly the FXR antagonist T-bMCA and T-vMCA) neuroblasts during their migration from the ventric-
(). Repopulation of mouse liver with human he- ular surface to their final location (). During the last
patocytes strongly induces FGF expression in the third of embryogenesis, FGF expression in the retina
ileum (). In rats, ileal interposition (surgical re- is progressively downregulated and is no longer de-
location of the distal ileum into the proximal jejunum) tected at  month of life (). FGF/FGFR sig-
causes a robust induction of FGF (). Vagotomy naling interplays with FGF signaling and the L-Maf
changes BA composition and increases passive ab- transcriptional system to regulate early lens develop-
sorption of BAs leading to induction of FGF in the ment ().
rat intestine (). In zebrafish embryos, the transcription factor
forkhead box C induces FGF expression in corneal
and periocular mesenchymal cells (). Loss of
Role of FGF15/19 in Development and FGF results in anterior segment structures within
Cellular Growth/Proliferation the eye () and a size reduction of the lens and the
retina (). FGF is involved in cell survival but not
Effects on fetal tissues in cell proliferation during embryonic lens and retina
Several members of the FGF family act in the early development ().
stages of embryonic development and during organ- In the pig, FGF is expressed in adult retinal
ogenesis to maintain progenitor cells and mediate their pigment epithelial cells and impacts proliferation/
growth, differentiation, survival, and patterning (). survival in photoreceptors (). In mice, FGF is
In addition to its endocrine functions, FGF/ is also expressed in the optic vesicle, a subset of pro-
also involved in numerous developmental processes, genitor cells of the neural retina, emerging ganglion,
mainly evidenced in the chick, zebrafish, or mouse and amacrine cells during retinogenesis ().
embryo. Survival of mice deficient in FGF depends
on the genetic background. Under the CBL/ Brain development
//Sv hybrid background, FGF knockout (KO) In the zebrafish, FGF is expressed in the forebrain,
mice are mostly embryonic lethal, because ,% of the midbrain, and hindbrain and is involved in cell

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REVIEW

proliferation and cell survival during embryonic brain (). Homology in the enhancers of the FGF and
development (). FGF appears essential for the FGF promoters suggests that FGF is also involved
specification of g-aminobutyric acidergic interneurons in the early development and distribution of cardiac
and oligodendrocytes generated in the ventral telen- neural crest cells, being a candidate gene for congenital
cephalon and diencephalon (). In the forebrain, heart defects in humans ().
FGF expression is downregulated on inhibition of
hedgehog signaling (). Effect on hepatocyte growth and proliferation
In mice, FGF is expressed from early neurulation The first evidence of a role for FGF in hepatocyte
in various zones of the neural tube, including the growth came from phenotypic observations in FGF
isthmus, the intrathalamic zona limitans, and the transgenic mice who developed locally invasive HCC

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anterior neural ridge (). FGF is initially present tumors by  to  months of age (). Hepato-
in domains where FGF is also expressed and, at later cellular proliferation, predominantly observed in
stages, in specific groups of neural cells (). In the pericentral hepatocytes, precedes tumor development
diencephalon and midbrain, FGF regulates pro- (). Similarly, acute FGF administration also in-
liferation and survival of dorsal cell populations by creases hepatocellular proliferation (). Further-
regulating the ability of dorsal neural precursors to more, FGF delivery through adeno-associated virus
respond to dorsally secreted Wnt mitogens (). (AAV) induces highly proliferative liver tumors with a
FGF is directly regulated by sonic hedgehog sig- latency depending on the mouse genetic background
naling through the GLI zinc finger transcription (). Hepatocarcinogenesis in FGF transgenic mice
factors (, ). Studies using FGF KO mice reveal can be prevented by monoclonal antibodies selectively
that FGF suppresses proliferation and promotes blocking the interaction of FGF with FGFR ()
neuronal differentiation and caudoventral fate (), or by genetic FGFR deficiency (). These results
showing opposite effects to FGF on neocortical strongly suggest that FGFR mediates the oncogenic
patterning and differentiation. In FGF KO mice, effect of supraphysiologic levels of FGF. In agree-
dorsal midbrain neural progenitors fail to exit the cell ment, molecular studies with truncated mutants of
cycle and to generate the requisite number of post- FGF and with FGF/FGF chimeric molecules
mitotic neurons due to altered expression of differ- also identify the FGF–FGFR interaction as the
entiation helix-loop-helix transcription factors (). mechanism driving hepatocyte proliferation and HCC
In fact, the expression of Id, Id, and Hes is strongly (, ).
increased and ectopically expanded, whereas the ex- Additional studies revealed the molecular and
pression of Ascl, Neurog, Neurog, and Neurod is cellular mechanisms underlying FGF-induced on-
strongly decreased in the dorsolateral midbrain of cogenicity. In vivo, as soon as  hours after a single
FGF KO mice compared with wild-type mice (). administration of FGF, the expression of key pro-
Moreover, FGF KO embryos exhibit a strong re- teins known to drive cell proliferation (such as TGF-
duction of FGFR expression in the alar prethalamus, b–induced protein ig-h, vascular cell adhesion
associated to a high proliferation rate of thalamic molecule , annexin A, and vigilin) are induced in
progenitors and disruption of thalamic neurogenesis mouse liver (). In vitro, FGF induces the ex-
(). FGF is a direct target of miR- in the fetal pression of the epidermal growth factor receptor
neural tube, and FGF overexpression is sufficient to ligand amphiregulin, which participates in the in-
drive precocious neural differentiation (, ). duction of the cycle cell regulator cyclin D ().
In humans, FGF could also harbor morphogenic FGF increases the invasive capabilities of human
properties in the brain, as suggested by its ability to HCC cell lines by promoting epithelial–mesenchymal
promote spontaneous generation of dorsoventrally transition via a GSKb–b-catenin pathway (, ).
polarized neural tube–like structures at the level of the Moreover, FGF facilitates cell survival through a
cerebellum in tridimensional embryonic stem cell resistance to apoptosis, involving GSKb activation
culture (). and nuclear accumulation of nuclear factor erythroid
–related factor  (). FGF increases the STAT
Heart development protein level and its phosphorylation (). This action
In mice, FGF is detected in the developing pha- is central to the proliferative properties of FGF. In
ryngeal arches, a region important for correct devel- fact, a modified FGF unable to induce STAT
opment of the aortic arch and cardiac outflow tract phosphorylation presents no mitogenicity and no
(). FGF KO mice present early morphological induction of pro-oncogenic target genes (). In
abnormalities of the outflow tract due to aberrant contrast to FGF, long-term overexpression of
behavior of the cardiac neural crest, resulting in heart FGF does not induce HCC in db/db and diet-
defects consistent with misalignment of the aorta induced obese (DIO) rodent models (). Again,
and pulmonary trunk (). In this context, FGF this is also due to the absence of upregulation of
operates through a pathway independent of Tbx, a STAT target genes in livers of mice overexpressing
master regulator of pharyngeal arches development FGF (). The hepatocellular ablation of STAT

970 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

blocks the initiation and progression of FGF- hepatocellular proliferation and fibrogenesis com-
dependent HCC formation (). In vivo and in vitro pared with wild-type mice (). FGF KO mice
observations suggest a non–cell-autonomous activa- show more advanced liver injury (and mortality
tion of STAT by FGF () and identify IL- depending on genetic background) following partial
originating from immune/Kupffer cells as a key in- hepatectomy (, ) or acetaminophen overdose
termediate relaying the protumorigenic activity of (). Of note, even if the downregulation of FGF/
FGF in mice (). –FGFR signaling can directly dampen hepato-
Several therapeutic approaches have been used to cyte regeneration, it can also have deleterious conse-
dampen the oncogenic FGF–FGFR signaling quences for liver integrity through derepressed BA
pathway. Functionally, clonal growth and tumorige- synthesis. Thus, liver alterations in FGF KO mice are

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nicity of HCC cells can be inhibited by knockdown of accompanied by persistently elevated intrahepatic BA
FGF through RNA interference, small hairpin RNA, levels (). Short interfering RNA–mediated
or neutralizing anti-FGF antibodies (, ). Anti- knockdown of FGFR also causes necrotic damage
FGFR monoclonal antibody inhibits tumor growth in due to intrahepatic overload of BAs (in particular of
mice bearing the HUH liver cancer cell line xenograft T-CA) following partial hepatectomy (). Accu-
(). BLU, a selective and irreversible small- mulation of BA in the liver in the context of FGF/
molecule inhibitor of FGFR, shows antitumor ac- FGFR inhibition could result from an imbalance
tivity in mice with an HCC tumor overexpressing between constitutive BA overproduction exceeding
FGF (). The selective covalent FGFR inhibitor, export capabilities. Another explanation could be a
HB-, tested in a large panel of HCC cell lines and change in BA transporters that are tightly controlled
patient-derived xenografted mouse models shows that by hepatic FXR activity, itself dependent on BA
FGF expression is a predictive biomarker for its composition.
response (). Cancer cell lines harboring a gain of Progression of liver HCC caused by FXR deficiency
FGF copy number and a concomitant expression can be prevented by the reactivation of intestinal FXR,
of KLB are sensitive to the selective FGFR inhibi- normalizing the FGF axis and BA homeostasis
tor NVP-BGJ (). ASP, an inhibitor of (). As for FGF/, BAs are also key players of the
FGFR–, potently suppresses the growth of several hepatostat (adjustment of liver size to the physiological “Several therapeutic
approaches have been used to
FGF-expressing hepatocellular carcinoma cell lines need) (), delineating direct and indirect (BA- dampen the oncogenic FGF19-
and induces sustained tumor regression in xenografted mediated) actions of FGF/. In this way, en- FGFR4 signaling pathway.”
mouse models (). Nevertheless, the strategy of hanced growth of livers of mice with humanized
inhibiting the FGF–FGFR pathway in HCC carries hepatocytes, which do not recognize FGF, is due
intrinsic safety risks. This represents a translational mainly to increased BA synthesis (). Nevertheless,
challenge with questions about the degree of blockade mice overexpressing FGF present very low BA levels
to achieve therapeutic benefits without inducing ad- but show increased hepatocyte proliferation in basal
verse hepatic/gastrointestinal toxicity in humans (). conditions and a further induction of cell-cycle pro-
Anti-FGF antibody demonstrated dose-related liver gression genes after partial hepatectomy (). This
toxicity and severe diarrhea in a safety study in cyn- demonstrates that FGF is critical in the phases of
omolgus monkeys (). The side effects seem to be priming and termination of liver regeneration, in-
related to increased BA synthesis, change in the ex- dependently of BA levels ().
pression of BA transporters in the liver and ileum, and
enhanced BA enterohepatic recirculation (). Effect on skeletal muscle growth
The blockade of elevated FGF levels or the in- FGF signaling is an important regulator of myogenesis
hibition of overactivated FGFR signaling could (–), but the involvement of endocrine FGFs in
present valuable antioncogenic properties. Never- this process was long unrecognized. A recent report
theless, FGF/ signaling can stimulate liver re- revealed a role for FGF in the regulation of skeletal
generation in case of increased demand. FGF muscle mass (). Treatment with FGF causes
administration promotes liver repair in mouse models skeletal muscle hypertrophy in mice leading to a better
of chemical liver injury or partial hepatectomy (), muscle strength (). Hypertrophy is not related to
even improving survival after extensive hepatectomy the numbers or the type of muscle fibers, but to a shift
(). An FGF/apolipoprotein A-I chimeric mole- toward larger myofibers (). In human myoblasts,
cule reduces liver injury and enhances regeneration in FGF does not affect cell proliferation or the ex-
acetaminophen-intoxicated or hepatectomized mice pression of classical myogenic factors, but it increases
(). Conversely, the lack of endogenous FGF the size of myotubes (). Muscular signaling in
can also be deleterious in situations of regenerative response to FGF stimulation includes the phos-
need. FGF KO mice have extensive liver necrosis phorylation of ERK/ and the ribosomal protein S
due to reduced hepatocyte proliferation and impaired kinase (). Interestingly, FGF ameliorates skeletal
cell cycle progression (). After administration muscle atrophy in obese and aged mice as well as in
of carcinogens, FGF KO mice present attenuated mice treated with glucocorticoids (), and therefore

doi: 10.1210/er.2018-00134 https://academic.oup.com/edrv 971


REVIEW

represents a promising strategy for increasing skeletal expression and reduced BA production (, ).
muscle mass in various human pathological condi- These observations initially suggested a hepatic
tions. Of note, FGF is devoid of muscular anabolic autocrine/paracrine role for FGF in the repression of
action, and muscle-specific KLB-deficient mice are BA production. Similarly, FGF is also involved in
refractory to the hypertrophic effect of FGF (). the negative feedback of BA synthesis. FGF ad-
Thus, FGF should act through the KLB–FGFR ministration decreases CYPA mRNA levels in wild-
complex in skeletal muscle, in line with previous re- type but not in FGFR KO mice (). Both FGF KO,
ports involving FGFR in myogenesis (–). FGFR KO, and KLB KO mice present elevated BA
production due to upregulation of CYPA in the liver
(, –). Further studies have highlighted the

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Role of FGF15/19 in Metabolism central role of the intestine in the negative feedback
model. Notably, ileal FGF expression negatively
Effect on liver and gallbladder correlates with hepatic CYPA expression in bile
duct–ligated mice (). Moreover, the FXR agonist
BA homeostasis GW significantly represses hepatic CYPA ex-
BAs are amphiphatic molecules produced by the liver pression in liver-specific FXR-deficient mice, but not
from cholesterol through two distinct synthesis in intestine-specific FXR-deficient mice (). This
pathways. In the classic (neutral) pathway, cholesterol demonstrates that activation of FXR in the ileum, and
a-hydroxylase (CYPA) is the rate-limiting and subsequent FGF release, is required for short-term
major regulatory enzyme (, ). Later steps in- CYPA repression. Of note, sterol a-hydroxylase
volve sterol a-hydroxylase leading to synthesis of expression is more dependent on direct negative
CA whereas other enzymes can alternately produce feedback by hepatic FXR than intestinal FXR–FGF/
CDCA (, ). In the alternative (acidic) pathway,  (, ). The role of FGF in the ileohepatic
cholesterol is only converted to CDCA (, ). negative feedback of BA synthesis is also supported by
CDCA is more hydrophobic than CA but is rapidly clinical observations. A postprandial increase in BA
metabolized into highly hydrophilic MCAs in rodents, levels triggers FGF secretion, which is followed by a
but not in humans (, ). All the primary (liver- decrease in BA synthesis (). Moreover, both pri-
derived) BAs are conjugated with taurine or glycine to mary BA malabsorption () and ileal resection ()
enhance their solubility and represent the main or- reduce FGF levels and increase BA synthesis.
ganic compounds of bile, secreted by the liver into the Beyond the regulation of the global level of BA
gallbladder for interprandial storage (, ). Meal production, ileohepatic FGF/–FGFR–KLB neg-
consumption triggers the release of bile into the du- ative feedback also impacts BA composition. FGF
odenum to allow emulsification and digestion of di- infusion in mice shifts BA synthesis from the neutral
etary lipids. BAs are actively reabsorbed in the ileum, to the alternative pathway, reducing the CA/CDCA
and they return to the liver through the portal cir- ratio (). Analogously, FGF injections increase the
culation, thus following an enterohepatic circulation MCA/CA ratio in mouse bile, inducing a more hy-
(, ). The few primary BAs escaping active ileal drophilic BA pool (). Treatment with the intestinal
reuptake reach the colon and are metabolized by gut FXR agonist fexaramine induces enteric FGF and
microbiota into secondary BAs (for example by leads to increases in LCA (a secondary BA derived
dehydroxylation of CA into DCA), which are passively from CDCA), at the expense of T-CA (, ).
absorbed by the colon or eliminated in the feces (, Nevertheless, this latter observation requires further
). Beyond their role in lipid assimilation, BAs have confirmation because substantial amounts of LCA in
hormonal actions throughout the body. Notably, BAs mouse plasma are not reported in others studies (,
bind and activate several receptors, mainly nuclear , , –).
FXR and membrane TGR (G-protein coupled BA On the contrary, mice with intestinal FXR de-
receptor ) BA receptors, both central regulators of ficiency exhibit very low FGF expression levels, an
glucose and lipid homeostasis (, ). increased proportion of CA and DCA, and a decreased
As biological detergents, BAs can be toxic and their proportion of b-MCA and v-MCA in bile (). This
production needs to be tightly regulated. In the he- leads to a rise in the BA hydrophobicity index com-
patocyte, FXR acts as the main BA sensor in charge of a pared with wild-type mice (). Mice with hepatocyte-
negative feedback, limiting BA production (, ). specific KLB deficiency exhibit an increased fraction of
Thus, CYPA is overexpressed in FXR-deficient mice CA in their BA pool (). In the same way, global KLB
(). A series of experiments has revealed that FGF KO mice exhibit a shift in BA production (). This
is central in the control of BA production. FGF modification is highlighted by activation of the clas-
expression is strongly induced by BA in human he- sical BA synthesis pathway at the expense of the al-
patocytes and, in turn, treatment with FGF reduces ternative pathway (). This leads to a predominant
the level of CYPA expression (, ). In the same representation of CA and DCA among circulating BAs
way, mice overexpressing FGF present low CYPA (). Similarly, in humans, BA sequestrants decrease

972 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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FGF levels and result in a preferential increase in CA without changing bile flow rate (). A weaker
synthesis at the expense of CDCA (). Taken to- stimulatory action of FGF/ in the filling of gall-
gether, these observations show that FGF/ neg- bladder is also observed in wild-type mice (). As no
ative feedback shifts BA synthesis from the neutral to FGF expression is detected in the liver, gallbladder,
the alternative BA synthesis pathway, both in mice and common bile duct, or sphincter of Oddi, this suggests
humans. In rodents, this results in a more hydrophilic that ileal-derived FGF acts as a hormone to stim-
BA pool due to the conversion of hydrophobic CDCA ulate gallbladder filling in mice (). The gallbladder
into highly hydrophilic MCA. In contrast, in humans, volume is also reduced in FGFR KO mice but to a
this generates a more hydrophobic BA pool. Con- lesser extent than in FGF KO mice, suggesting that
versely, attenuation/abrogation of FGF/ signaling other FGFRs contribute to the actions of FGF on the

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enriches the BA pool in a-hydroxylated BAs such as gallbladder (). In the same way, gallbladder volume
CA or DCA. This results in a relatively more hy- is reduced in KLB KO mice, which exhibit a resistance
drophobic BA pool in rodents and a more hydrophilic to gallstone formation (). Postprandial circulating
BA pool in humans (with CA being more hydrophilic cholecystokinin concentrations are lower in FGF
than the persistent CDCA). As a consequence, FGF/ KO mice compared with wild-type mice, demon-
 signaling can change not only BA levels, but also BA strating that this classic bile-releasing factor is not
species distribution. Therefore, modification in the involved in the action of FGF (). In contrast,
composition of the BA pool also impacts the in- FGF completely blocks contraction of the gall-
tracellular signaling through the BA receptors FXR bladder caused by cholecystokinin (). FGF and
and TGR. FGF stimulate gallbladder filling at least in part by
As a gatekeeper of BA production, FGF can causing a cAMP-dependent relaxation of gallbladder
represent a therapeutic opportunity to treat diseases smooth muscle (). In humans, after CDCA
related to BA dysregulation. However, the proliferative administration, a progressive increase over time in
action of FGF on hepatocytes represents a major risk both FGF levels and gallbladder volume is observed
to treating hepatobiliary disorders. To overcome this both in control subjects and in patients with intestinal
therapeutic limitation, molecular reengineering of the diseases ().
FGF molecule allows dissociation of the proliferative The high concentration of FGF in human bile “FGF19 can represent
a therapeutic opportunity to
and metabolic properties of the molecule. The ge- (, ), originating from the gallbladder itself and the treat diseases related to BA
netically modified FGF M carries three amino extrahepatic bile duct (, ), contrasts with the dysregulation.”
acid substitutions (AS, GS, and HL) and a absence of FGF in mouse bile. The role of this
five–amino acid deletion. This FGF variant exhibits exocrine secretion remains poorly studied. It has been
the same biological activity as FGF, including suggested that biliary FGF can protect against
FGFR binding, ERK signaling, and suppression of detrimental effects of BAs or regulate mucin expres-
CYPA, without tumorigenicity (). M protects sion in tissues exposed to concentrated bile (). This
mice from liver injury induced by either extrahepatic action can explain species differences because mice,
or intrahepatic cholestasis (, ). AAV-mediated devoid of biliary FGF, have a less toxic/hydrophobic
delivery of M rapidly attenuates liver injury, in- BA composition than do humans.
flammation, biliary fibrosis, and cholelithiasis in mice
deficient for the canalicular phospholipid flippase Nutrient partitioning in postprandial and
(MDR KO mice) (). The hepatosplenomegaly and fasted states
ductular proliferation associated with cholangiopathy In response to BA and nutrients reaching the intestine
are also improved with M administration (). during digestion, FGF gene expression gradually
From a translational point of view, M potently increases in the mouse ileum, peaking around  hour
reduces circulating levels of a-hydroxy--cholesten- postgavage (). In humans, circulating FGF
-one in healthy volunteers (). This reflects a concentration peaks  to  hours following a meal
dampening of CYPA activity in humans with the (, ), with an approximate half-life of  minutes
perspective of treating disorders of BA dysregulation (). This food-driven pattern of regulation suggests
(). To date, M (also named NGM) is the only that FGF/ can act as a hormone of the fed state. In
FGF analog tested in clinical trials in patients suf- fact, administration of FGF significantly increases
fering from primary biliary cirrhosis and diabetes protein synthesis and glycogen accumulation in the
(). liver of fasted mice (). In contrast, fed FGF KO
mice have half the hepatic glycogen stores compared
Gallbladder filling with wild-type mice (). This effect of FGF/ is
Another main function of FGF/ in BA homeo- similar to, but independent of, insulin action. In fact,
stasis relates to the filling of the gallbladder. The postprandial peak of FGF levels is delayed compared
gallbladder of the FGF KO mouse is almost devoid with the insulin peak (). Additionally, insulin in-
of bile, and administration of FGF or FGF creases hepatic FGFR levels (), suggesting a
causes a .-fold increase in gallbladder volume, priming of FGF action. Both hormones work in a

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REVIEW

coordinated, temporal fashion to facilitate the proper the same context (). Of note,  to  weeks of FGF
storage of nutrients after a meal (). Even if FGF administration transiently increase circulating tri-
signaling decreases FoxO activity, as does insulin (), glycerides and cholesterol levels in ob/ob mice and in
the intracellular signaling pathways used by FGF DIO mice (). This action is also observed with a
and insulin show differences. FGF activates the Ras/ modified FGF (), only activating FGFR, and
ERK/MAPK-interacting protein kinase /pRSK could be directly related to the inhibition of BA
pathway, whereas insulin signals through phosphati- production. In fact, treatment with BA binding resins
dylinositol -kinase/Akt/mTOR/pSK, allowing (, ), as well as CYPA deficiency (), in-
overlapping but distinct biological actions for both creases triglyceride levels. However, this effect remains
hormones (). transitory, suggesting that it is gradually overcome by

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Unlike insulin, FGF does not acutely increase the more chronic extrahepatic lipid-lowering action of
hepatic triglycerides in the postprandial state, thus FGF ().
uncoupling carbohydrate and lipid storage (). Taken together, these results suggest that activation
Furthermore, in rat primary hepatocytes, FGF of the FGF/ signaling pathway present potential
suppresses the expression of lipogenic enzymes and opportunities with respect to hepatic steatosis. Nev-
represses the insulin lipogenic action (through in- ertheless, the abrogation of endogenous FGF sig-
creasing STAT activity and decreasing PPAR-g naling does not result in an inverse hepatic fat
coactivator b expression) (). In fasted mice, in- overload. In fact, both FGFR KO mice and KLB KO
jection of FGF decreases the expression of proteins mice exhibit few modifications of hepatic lipid content
involved in fatty acid synthesis and increases the ex- on a chow diet, and they are resistant to hepatic
pression of proteins involved in fatty acid oxidation steatosis on an HFD (, , , ). A possible
(). FGF/ also inhibits the expression of one- explanation for this protection can be the modification
carbon cycle genes, critical determinants of hepatic in BA levels/composition. In fact, mice overexpressing
lipid levels (), and mediates postprandial epigenetic CYPA present a similar pattern of BAs as do KLB
repression of hepatic autophagy (). KO mice and exhibit the same resistance to hepatic
In addition to its action during the fed state, steatosis (). The underlying mechanisms could
FGF/ suppresses hepatic metabolic pathways, involve changes in FXR signaling in the liver [known
which are active during fasting, including gluco- to repress de novo lipogenesis ()] or activation of
neogenesis and the tricarboxylic acid cycle flux (). TGR signaling in BAT (driving thermogenic lipid
This hepatic action is mediated through decrease use) (). Thus, if FGF/ signaling presents direct
of the activity of transcription factor cAMP regula- antilipogenic actions in the long-term, its blockade
tory element–binding protein and downregulation also leads to attenuation of hepatic lipid storage
of PPAR-g coactivator a and its gluconeogenic/ through the modification of the BA pool. Of note,
oxidative target genes (). In agreement, FGF FGF can also interfere with the secretory function of
KO mice and FGFR KO mice exhibit increased the liver, regulating the expression of its sister mol-
gluconeogenesis and higher glycemia than do wild- ecule FGF (), as well as antiatherogenic and
type mice after refeeding (). atherogenic proteins (–).

Hepatic lipid storage Effect on whole-body energy and


The concomitant role of FGF/ in the control of glucose homeostasis
BA production and nutrient partitioning raises Several genetic and pharmacological studies in mice
questions about its long-term effects on hepatic lipid have demonstrated the beneficial action of FGF/
metabolism. FGF transgenic mice present a reduced in energy balance. Transgenic mice overexpressing
expression of lipogenic enzymes and triglyceride FGF are leaner than wild-type mice, exhibiting
content in the liver (). Treatment with the long- decreased fat content despite higher food intake ().
lasting FGF/apolipoprotein A-I chimeric molecule This phenotype is explained by higher oxygen con-
also reduces liver lipid accumulation in vivo and sumption (with no change in the respiratory quotient,
protects hepatocytes against endoplasmic reticulum reflecting the proportion of carbohydrates and lipids
stress and cytotoxicity induced by palmitic acid in vitro used) and is also associated with an increased insulin
(). In mice fed a high-fat, high-fructose, high- sensitivity (). FGF overexpression also confers
cholesterol diet, reengineered FGF M reduces resistance to DIO and can alleviate the genetic obesity
hepatic levels of toxic lipid species (diacylglycerols, in ob/ob mice, partly due to the increase in BAT
ceramides, and free cholesterol) and increases levels of activity (). AAV delivery of FGF and FGF also
unoxidized mitochondrial cardiolipins (). In line allows investigation of their global metabolic actions.
with a FGF/-mediated repression of liver fat Both FGF and FGF overexpression reduce fat
storage, FGF KO mice also exhibit exacerbated mass and increase energy expenditure in DIO mice,
hepatic steatosis when fed an HFD () although but FGF appears more potent (). FGF over-
other studies only report an attenuation of fibrosis in expression, but not FGF overexpression, reverses

974 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

diabetes in db/db mice (independently of weight loss) mouse brain is nonlinear, nonsaturable, and affected
(). Moreover, endogenous FGF does not influence by its blood concentration (). Peripheral delivery
body weight homeostasis through extrahepatic action. of FGF triggers ERK signaling in the hypothalamus
In fact, hepatocyte-specific KLB KO mice present high (). FGFR and FGFR are both present in rat
FGF levels but gain similar weight to wild-type mice hypothalamus (). KLB is also expressed in the
on an HFD (). As with genetic overexpression, mouse hypothalamus (in particular in the supra-
short-term ( week) pharmacologic administration of chiasmatic and paraventricular nuclei), in the hindbrain
FGF exerts systemic metabolic actions. IV admin- (in the area postrema and the solitary nucleus), and
istration of FGF ( mg/kg) increases the metabolic in the nodose ganglia of the periphery (, ).
rate and fat oxidation in mice on an HFD, without Taken together, these nuclei expressing KLB include

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modifying food intake (). Treatment with IP the dorsal–vagal complex, a major integrative center
FGF ( mg/kg) reduces body weight and enhances for the autonomic nervous system (). Although
glucose utilization in both DIO and ob/ob mice (, of primary interest, these observations in murine
). The improved glycemia obtained through sub- studies require caution regarding their translation to
cutaneous FGF infusion ( mg/kg) occurs in- humans.
dependently of any change in body weight in ob/ob The first evidence of a brain-mediated FGF
mice (). metabolic activity comes from central injections of
Taken together, these metabolic observations FGF into the lateral ventricle in mice, which pro-
suggest that FGF represents an interesting can- duce an increase in the metabolic rate comparable to
didate for treatment of obesity and TD. Modified systemic administration (). This observation is
forms of FGF have also dissociated its effects on confirmed by central FGF delivery, which stimulates
lipid and glucose metabolism. FGF (FGF-) sympathetic outflow to BAT and increases energy
retains the ability to stimulate glucose uptake in expenditure (). Moreover, studies involving ge-
vitro and in vivo in ob/ob mice without inducing netically modified mice also support a central action
FGFR-mediated hepatocyte proliferation (). for FGF. In fact, mice harboring KLB deficiency in
FGFv, which activates KLB/FGFRc, but not the central nervous system are refractory to body
KLB/FGFR, reduces blood glucose levels and weight and glycemia improvements induced by “Transgenic mice
therefore improves glucose tolerance (). Similarly, FGF, whereas mice with hepatocyte- or adipose- overexpressing FGF19 are
FGF-, presenting a preferred selectivity for specific KLB deficiency remain sensitive to FGF leaner than wild-type mice.”
FGFRc, is equally effective as wild-type FGF in action ().
regulating glucose, lipid, and energy metabolism in Mechanistically, some studies suggest that central
DIO and ob/ob mice (). In contrast, FGFdCTD, FGF/ signaling interferes with neuronal control of
which activates only FGFR, but not FGFRc, insulin and glucagon secretion, whereas other studies
FGFRc, or FGFRc, represses BA synthesis, but it highlight a role in the hypothalamic–pituitary–adrenal
fails to improve glucose levels and insulin sensitiv- axis or glucose effectiveness (insulino-independent
ity in ob/ob mice (). Moreover, infusion of FGF glucose use).
at supraphysiological levels improves glucose toler- Intracerebroventricular (ICV) FGF injections
ance (independently of body weight) to a similar for  days reduce body weight and improve both
extent in wild-type and FGFR KO mice, indicating glucose-induced insulin secretion and insulin sen-
that FGFR is not required for glucose lowering (). sitivity in DIO mice (). This involves activation of
Taken together, these results demonstrate that in ERK/ signaling and repression of agouti-related
contrast to the repression of BA synthesis mediated protein/ neuropeptide Y (NPY) neuron activity ().
through FGFR, the glucose lowering action of Thus, FGF/ partially recapitulates the central
(pharmacologic) FGF is mediated by FGFR. action of leptin. Recent insights also suggest that
Other studies revealed that the glucose lowering hypothalamic FGF/ signaling can be antag-
action of FGF involves FGFR expression, not in onized by paracrine FGF produced within the
the adipose tissue (), but rather in the central hypothalamus (). Moreover, acute FGF ad-
nervous system (). ministration into the third cerebral ventricle in rats
reduces daily food intake and body weight, and
Effect on brain impacting body energy and acutely improves glucose tolerance (). Con-
glucose homeostasis versely, administration of an FGFR– antagonist
Numerous gut-derived hormones act on the central increases food intake and impairs glucose tolerance
nervous system to elicit their metabolic effects, in- (). It involves transient sympathoadrenal acti-
cluding the control of food intake, energy expen- vation and a reduction of insulin secretion ().
diture, and glucose tolerance (, ). This Another role for central FGF has recently emerged
suggests a possible involvement of FGF/ in the in glucose counterregulation. ICV injections of
metabolic gut–brain axis. In contrast to specific FGF reduce the neuroglucopenia-induced acti-
uptake of FGF in the liver, influx of FGF into vation of the dorsal vagal complex neurons and the

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REVIEW

parasympathetic nerve, thus lowering glucagon se- FGF19 in Human Diseases


cretion (). Alternatively, silencing FGF expres-
sion in the dorsomedial hypothalamus increases Obesity and diabetes
neuroglucopenia-induced glucagon secretion ().
A single, low-dose ICV injection of FGF Obesity
improves glucose intolerance within  hours in ob/ Several studies have reported that basal circulating
ob mice, independently of changes in energy bal- FGF levels are significantly lower in obese patients
ance (). This direct antidiabetic action is due to relative to nonobese controls, without any strong
increased peripheral glycolysis and is independent relationship to glucose metabolism or insulin sensi-
of changes in insulin secretion or insulin sensitivity tivity (, –). This suggests that excessive

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(). In the same way, acute ICV injections of weight in itself drives the decrease in FGF levels. In
FGF reduce plasma glucose, corticosterone, and this way, FGF levels are mainly correlated to visceral
ACTH, independently of any change in plasma adiposity (, ). Moreover, expression of KLB is
insulin and glucagon, in an insulinopenic rat model significantly decreased in the visceral adipose tissue of
of TD (). In this study, FGF suppresses obese patients, whereas it is increased in their liver
hepatic glucose production by reducing hepatic (). Nevertheless,  weeks to  months of lifestyle-
acetyl CoA levels (). Indeed, the glucose- induced weight loss does not consistently restore basal
lowering action of FGF is due to the suppres- and postprandial circulating levels of FGF (, ,
sion of the hypothalamic–pituitary–adrenal axis ).
(). In line with the insulin-independent glucose
lowering effect of FGF/ signaling, FGF KO Type 2 Diabetes
mice show impaired glucose uptake from the cir- Other studies report that basal circulating FGF
culation () and more elevated postprandial gly- levels are inversely correlated to glucose metabolism or
cemia compared with wild-type mice, without any insulin sensitivity. Notably, patients with metabolic
change in insulin sensitivity or glucagon concen- syndrome or TD have lower circulating FGF levels
trations (). than do healthy controls (, , ). Moreover,
Pleiotropic functions of FGF/ in animals and basal FGF levels are negatively associated with
humans are illustrated in Fig. . fasting glycemia and independently associated with the

Figure 4. Pleiotropic
functions of FGF15/19 in
animals and humans.
Stimulatory effects are
indicated by plus signs (+),
inhibitory effects by minus
signs (2). Data are derived
from clinical observations/
studies and cell cultures in
humans (h) and experimental
studies and cell cultures in
mice (m), rats (r), chickens (c)
and zebrafish (z). FFA, free
fatty acid; TG, triglyceride.
[© 2018 Illustration
Presentation ENDOCRINE
SOCIETY].

976 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

deterioration of glucometabolic status (). Patients particular with conjugated CA), as well as with disease
with TD have lower circulating FGF levels than do severity ().
nondiabetic patients, irrespective of body weight ().
Circulating levels of FGF are also significantly re- Cholelithiasis/primary sclerosing cholangitis
duced in women with gestational diabetes mellitus The expression of FGF is reduced in ileal biopsies of
relative to healthy pregnant women (). gallstone carriers with normal weight (), but cir-
culating FGF levels are not related to the history of
Liver and biliary diseases cholecystectomy (). A marked elevation of circu-
lating FGF levels is observed in patients with ex-
NAFLD trahepatic cholestasis caused by a pancreatic tumor

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Some studies report that patients with NAFLD (). In patients with sclerosing cholangitis, basal
present similar basal FGF levels to healthy sub- FGF levels are unchanged (). However, these
jects (, ). Nevertheless, their hepatic response patients exhibit a prolonged FGF peak in the cir-
to FGF is impaired when they present insulin culation following a CDCA oral challenge () as well
resistance (). Other studies show that FGF as increased FGF protein content in the ascending
levels are significantly lower in patients with colon (). UDCA withdrawal does not change
NAFLD than in controls (, ). This decrease circulating FGF levels in patients with primary
could be related to reduced FGF production sclerosing cholangitis ().
caused by a disproportionate increase in the amount
of DCA at the expense of CDCA (a most potent FXR Intestinal diseases
agonist) (). In obese adolescents with NAFLD,
FGF levels are dampened compared with controls, Patients with BA malabsorption
with an inverse correlation between FGF, alanine BA malabsorption leads to excessive fecal BA excre-
aminotransferase, and triglyceride levels (). In tion and diarrhea. It is also associated with lack of
children with NAFLD, serum FGF is inversely feedback regulation, resulting in additional BA pro-
associated with hepatic damage (, ). KLB duction, saturating ileal transport. Circulating FGF
expression decreases in children livers with in- levels are significantly lower in patients with BA
creasing severity of NAFLD (). malabsorption compared with controls (, , ),
In a recent phase  clinical study, the reengineered whereas a subgroup of hypertriglyceridemic patients
FGF analog NGM (also known as M in presented higher values (). Impairment in ileal
preclinical studies) produced a rapid and significant FGF expression and responsiveness contributes to
reduction in liver fat content in patients with NASH the multifactorial etiology of primary BA diarrhea
(). In fact, after  weeks of treatment ( or  mg (–). FGF represents both an opportunity for
SC) % of patients achieved a reduction of .% in diagnosis and treatment of the pathophysiological
fat content, associated with significant reductions in defect. From a genetic point of view, a DIET coding
both alanine aminotransferase and aspartate amino- variant, which increases the amount of FGF se-
transferase (). Liver fat content is completely creted, has a skewed prevalence between patients with
normalized in % to % of patients (). BA diarrhea and controls (), suggesting that genetic
variation impacting FGF secretion also affects BA
Cirrhosis metabolism in pathological conditions ().
FGF expression is increased in cholestatic non-
cirrhotic and cirrhotic livers compared with control Inflammatory bowel syndrome
livers (, ). Both circulating and hepatic levels of Patients with inflammatory bowel syndrome (IBS)
FGF correlate with the severity of hepatic disease have similar FGF levels to controls (, ), but a
(). Circulating FGF levels are higher in cirrhotic subset of IBS patients with low BA turnover rate
patients with primary biliary cirrhosis compared with presents lower FGF levels (). Variants in KLB
noncirrhotic patients with primary biliary cirrhosis or and FGFR may identify subgroups of patients
healthy individuals (). FGF levels are strongly with IBS showing () elevated serum a-hydroxy-
correlated with BA synthesis and the severity of -cholesten--one (), () changes in BA/colonic
cholestasis (). Administration of the FXR agonist transit (, ), or () a positive response to
obeticholic acid increases FGF levels in patients with treatment with BA sequestrants (). In pediatric
primary biliary cirrhosis and improves markers of the onset of intestinal failure, total or partial loss of the
disease, such as the alkaline phosphatase and total ileum decreases circulating FGF levels (, ). In
bilirubin levels (). In patients with alcoholic hep- these patients, FGF levels negatively correlate with
atitis, circulating FGF levels are strongly increased the extent of portal inflammation, serum TNF-a, and
and gene expression of FGF is induced in biliary hepatic fibrosis stage (). Low FGF levels are also
epithelial cells and ductular cells (). FGF levels associated with liver injury featured by liver bile duct
correlate positively with total and conjugated BAs (in proliferation, inflammatory infiltration, predominance

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REVIEW

of primary BA, hepatocyte apoptosis, and fibrosis especially in patients infected with hepatitis B ().
(). Reduced FGF levels are associated with ileal FGF amplification is also observed at advanced
resection, diarrhea, and Crohn’s disease activity, stages in aggressive HCC tumors (). A gain in
suggesting a role of FGF as a biomarker for diseases FGF copy number is detected more frequently
affecting the ileum (). FGF levels are decreased in among patients with a complete response to the
patients with Crohn’s disease when compared with multikinase inhibitor sorafenib compared with pa-
healthy controls, or even when compared with patients tients with incomplete response (). Genetic alter-
with ulcerative colitis (). ations in FGFR, including frequent polymorphisms,
are also observed in HCC tissues compared with
Renal diseases control tissue pairs (). In vitro FGF stimulation

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Circulating FGF levels are increased during end- confirmed a mechanistic link between FGFR activ-
stage renal disease in patients undergoing chronic ities and tumor aggressiveness in HCC cell lines ().
hemodialysis compared with normal subjects (). The inhibition of FGF/FGFR signaling overcomes
The postprandial FGF response is also blunted in sorafenib resistance (, ). In a genome-wide
patients with chronic kidney disease compared with mapping of DNA methylation, the FGF gene ap-
control subjects, in association with impaired insulin pears significantly hypermethylated in the tumor tis-
and C-peptide signaling (). sues compared with paired adjacent peritumoral
tissues (). Therapeutic approaches targeting FGFR
Cancer in HCC, including ongoing clinical trials, have been
previously reviewed ().
HCC
The action of FGF on hepatocyte proliferation Digestive tract cancers
observed in mice and cell culture suggests a role in the FGF is overexpressed in gastric cancer and is as-
occurrence or progression of HCC in humans. FGF sociated with depth of invasion and lymph node
and FGFR are coexpressed in primary human liver metastasis (). In vitro, FGF enhances migration
tumors (). FGFR expression is elevated in liver and the invasion abilities of gastric cancer cells ().
tumors relative to normal tissues (). FGF is FGF and FGFR are coexpressed in primary
equally significantly overexpressed in HCC compared human colon tumors and in a subset of human colon
with corresponding noncancerous liver tissue and is an cancer cell lines (). In these cells, FGF increases
independent negative prognostic factor for survival tyrosine phosphorylation of b-catenin and inhibits
(, , , ). Expression of FGF is associated b-catenin/E-cadherin binding (), suggesting that
significantly with larger tumor size () and correlates inactivation of FGF/FGFR signaling could be a
with sensitivity of cells to FGFR inhibitors (). therapeutic target. FGF is required for PXR-induced
Hepatic tissue protein content of FGF and FGFR cell growth, invasion, and metastasis in both human
significantly correlates with histopathologic changes colonic tumor cell lines and mice xenografted with
from fatty liver to HCC (). FGF levels are also tumor cells (). PXR binds to the FGF promoter
significantly increased in the circulation of patients in human colon tumor cells as well as in normal
with HCC compared with controls () and are intestinal crypt cells, but promoter activation occurs
lowered after surgical tumor resection (). A only in cancer cells ().
positive correlation is observed between the ex- The implication of FGF in pancreatic tumors
pression of FGF and the epidermal growth factor and cholangiocarcinoma remains more elusive.
receptor ligand amphiregulin (), whereas FGF FGFR expression is markedly increased in high-grade
expression is negatively associated with the expres- pancreatic ductal adenocarcinoma and pancreatic
sion of E-cadherin in HCC tissues (), thus intraepithelial neoplasia compared with the nor-
highlighting a role in epithelial–mesenchymal tran- mal pancreas (). FGF seems to contribute to
sition. FGF expression is also correlated with the tumor suppression by increasing cellular adhesion
expression levels of STAT target genes in HCC to the extracellular matrix in pancreatic ductal ad-
tumors (). High expression of FGF signaling enocarcinoma cells (). FGF expression is re-
actors and low expression of FGF signaling re- duced in cholangiocarcinoma tumors compared with
pressors correlate with the aggressiveness of hep- normal bile duct tissue (). In intrahepatic chol-
atoblastoma tumors in children (). angiocarcinoma, high expression of FGF is signifi-
In addition to the overexpression of FGF in cantly associated with better survival ().
hepatic tumors, amplification of the FGF gene re-
gion is also observed in HCC, corroborating a role as a Reproductive tissues cancers
tumor-promoting gene (). Genomic profiling of In addition to hepatic and gastrointestinal cancers,
HCC at early stages reveals high copy number am- several studies have implicated FGF in cancers of
plifications of the gene region, including the FGF reproductive tissues, including the prostate, ovary, and
gene in % of cases, in association with liver cirrhosis, breast.

978 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
REVIEW

FGF is expressed in primary and metastatic Conclusions and Perspectives


prostate cancer tissues, where it functions as an
autocrine growth factor (). Exogenous FGF Human FGF and its murine FGF homolog are
promotes growth, invasion, adhesion, and colony fascinating hormones harboring a wide diversity of
formation of prostate cancer cells (). In contrast, actions, from fetal morphogenesis to stimulation
FGF silencing in prostate cancer cells expressing of adult tissue growth (liver, muscle), through control
autocrine FGF decreases invasion and pro- of BA synthesis and insulin-like postprandial activity.
liferation in vitro and tumor growth in vivo (). Moreover, administration of supraphysiological doses
Moreover, higher levels of prostate-specific antigen of FGF strikingly mimics the effects of FGF,
are observed in patients with prostate tumors increasing energy expenditure and glucose utilization.

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positive for FGF staining, and survival is higher in These biological properties explain the strong scientific
patients with FGF-negative tumors (). FGF enthusiasm for these molecules and the optimism
enhances the viability and the expression of concerning their use as metabolic drugs.
N-cadherin in human prostate adenocarcinoma Based on the evolutionary conservation of their
cells while suppressing the expression of E-cadherin surrounding genetic loci, FGF and FGF genes are
and caspase  (). considered as orthologs (). However, their homol-
High expression of FGF predicts unfavorable ogy is weaker than all other human/mouse FGF family
prognosis of advanced-stage serous ovarian cancer members (), suggesting some divergence in terms of
(). In vitro, FGF promotes ovarian cancer cell production and biological actions. FGF and FGF
proliferation and invasion by activating the FGFR– are both highly expressed in the ileum. In the liver,
Akt-MAPK signaling pathway (). FGF is absent in mice (, ) but FGF is induced
FGF is also involved in breast cancer (). in humans under cholestatic conditions (–, ,
FGFR/FGF coexpression is observed in almost one ), raising questions about this tissular contribution.
third of primary breast tumors (). A subset of basal- Additionally, high levels of FGF are observed in
like breast cancer cells secretes FGF, and FGFR is a human bile (, ) due to high production levels in
mediator of cell survival via activation of phosphati- gallbladder cholangiocytes and extrahepatic bile duct
dylinositol -kinase/Akt signaling (). The YC (, ). This suggests either an exocrine or a paracrine “Several studies have
missense mutation in FGFR in a human breast cancer function (anti-inflammatory, secretagogue?), which implicated FGF19 in cancers of
cell line confers insensitivity to FGFR ligand stim- remains to be elucidated. Molecular regulation of reproductive tissues.”
ulation, but it elicits a constitutive phosphorylation FGF and FGF also reveal some differences, in
leading to activation of the MAPK cascade–driven particular concerning the nuclear receptors involved.
tumor growth (). Furthermore, the role of gut microbiota in the reg-
ulation of FGF/ is not fully elucidated in mice and
Other cancers is presently unknown in humans.
FGF expression is observed in most malignant cells Beyond their regulation, FGF and FGF also
of patients with thyroid cancer (). The amount of present structural divergences. Of note, FGF
FGF protein in thyroid cancer tissues is signifi- contains a specific unpaired cysteine residue, which
cantly higher than in normal tissues (). FGF allows dimerization of FGF monomers (). Thus,
overexpression is also significantly associated with conformational divergence between FGF and
advanced stages of the disease, including tumor node FGF could induce differences in ligand–receptor
metastasis, extrathyroidal invasion, and distant me- affinity and explain functional disparities. The sys-
tastasis (). Amplification of the FGF genic re- temic effect of FGF has long been underinvestigated
gion is observed in a subset of patients with advanced due to the instability of the molecule (, , ). In
medullary thyroid carcinoma (). Higher circu- contrast, human FGF has been intensively studied in
lating levels of FGF are found in patients with mice, albeit with concerns about technical bias and
papillary thyroid cancer, follicular thyroid cancer, limitations associated with the use of human FGF in
and anaplastic thyroid cancer when compared with murine models (expressing mouse FGFRs). Moreover,
patients with multinodular nontoxic goiter and with clinical studies, as well as human primary cultures,
healthy controls (). FGF is equally highly reveal some differences from what is observed in
expressed in mesenchymal stem cells/exosomes, mice, complicating the translation of mouse-derived
which accelerates nasopharyngeal carcinoma pro- knowledge to the human situation. The understanding
gression (). FGF and FGFR are also coex- of the role of FGF/ in metabolism is further
pressed in primary human lung tumors (). In complicated by the fact that beyond metabolic con-
patients with lung squamous cell carcinoma, am- sequences directly resulting from FGFR signaling,
plification of the FGF genic region, as well as gene FGF/ also modulates levels and composition of
overexpression in the tumor compared with adjacent BAs, master regulators of energy expenditure, as well
nontumoral tissues, is found more frequently with as lipid and glucose metabolism. In fact, both FGF
smoking (, ). and FGF repress hepatic BA production and shift

doi: 10.1210/er.2018-00134 https://academic.oup.com/edrv 979


REVIEW

BA synthesis from the neutral to the alternative BA synthesis in humans () and is currently being tested
synthesis pathway. However, owing to differences in in patients suffering from primary biliary cirrhosis and
BA metabolism among species, FGF action in- TD (). More recent studies demonstrate that M
creases hydrophilicity of the BA pool in rodents, reduces hepatic fat content in patients with NASH in a
whereas FGF increases hydrophobicity of the BA phase  clinical trial (), currently representing the
pool in humans. This effect on BA composition also most significant advance in the use of FGF as a drug.
impacts differently FXR and TGR signaling in mice FGF has grown in interest for treating obesity
and humans and deserves further metabolic in- and TD (). Nevertheless, it is already upregulated
vestigation. New animal models more closely mim- during metabolic diseases, reflecting either a com-
icking human physiology in terms of BA biology could pensatory mechanism to limit metabolic insults or a

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provide functional and mechanistic insights that better state of FGF resistance. In contrast, FGF levels are
delineate particular clinical situations. FGF appears decreased in human metabolic diseases, including
more potent than FGF for correcting murine obesity obesity (, –), TD (, , , , ), or
(). However, unlike FGF, FGF induces hepa- NAFLD (, ). Even if these clinical studies are
tocyte proliferation and ultimately HCC in mice (). correlative in nature and do not provide mechanistic
This side effect has dampened the interest of several explanations, they support supplemental approaches
pharmaceutical companies for FGF, leading them to to treat metabolic and hepatic diseases. Moreover, in
focus on nonmitogenic FGF as a metabolic drug addition to its FGF-like glucose lowering ac-
candidate. The action of FGF on hepatocyte pro- tivity, FGF could also be beneficial in diseases
liferation is directly dependent on STAT activation involving BA excess or gut-related FGF de-
and downstream target genes (, , ). Reengin- ficiency. Alternatively, FGF is overexpressed in
eering of FGF allows suppression of its ability to HCC tumors compared with corresponding con-
induce STAT phosphorylation and thus its onco- trol hepatic tissue (, , , ). This suggests
genicity (). Thus, genetically modified FGF (M) that inhibition/blockade of FGF signaling can
retains biological properties and protects mice from also be beneficial in this pathological context in
cholestatic liver injury (, , ). From a trans- which novel therapeutic approaches are also ur-
lational point of view, this compound also reduces BA gently needed.

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Meric-Bernstam F, Kurzrock R. Unique molecular 363. Motylewska E, Ste˛pień T, Borkowska M, Kuzdak K, Correspondence and Reprint Requests: Emmanuel
signatures as a hallmark of patients with met- Siejka A, Komorowski J, Ste˛pień H, Ławnicka H. Somm, PhD, or François R. Jornayvaz, MD, Service of En-
astatic breast cancer: implications for current Alteration in the serum concentrations of FGF19, docrinology, Diabetes, Hypertension, and Nutrition, Geneva
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359. Tiong KH, Tan BS, Choo HL, Chung FF, Hii LW, Tan 364. Shi S, Zhang Q, Xia Y, You B, Shan Y, Bao L, Li L, E-mail: emmanuel.somm@unige.ch or Francois.Jornayvaz@
SH, Khor NT, Wong SF, See SJ, Tan YF, Rosli R, hcuge.ch.
You Y, Gu Z. Mesenchymal stem cell-derived
Cheong SK, Leong CO. Fibroblast growth factor Disclosure Summary: The authors have nothing to
exosomes facilitate nasopharyngeal carcinoma
receptor 4 (FGFR4) and fibroblast growth factor 19 progression. Am J Cancer Res. 2016;6(2):
disclose.
(FGF19) autocrine enhance breast cancer cells
459–472.
survival. Oncotarget. 2016;7(36):57633–57650. Abbreviations
365. Tan Q, Li F, Wang G, Xia W, Li Z, Niu X, Ji W, Yuan
360. Roidl A, Foo P, Wong W, Mann C, Bechtold S, Berger

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H, Xu Q, Luo Q, Zhang J, Lu S. Identification of AAV, adeno-associated virus; BA, bile acid; BAT, brown ad-
HJ, Streit S, Ruhe JE, Hart S, Ullrich A, Ho HK. The ipose tissue; CA, cholic acid; CDCA, chenodeoxycholic acid;
FGF19 as a prognostic marker and potential
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MDA-MB453 breast cancer cells. Oncogene. 2010; driver gene of lung squamous cell carcinomas in
DIO, diet-induced obesity; E, embryonic day; FGF, fibroblast
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receptor substrate 2a; FXR, farnesoid X receptor; GSK, gly-
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cogen synthase kinase; HCC, hepatocellular carcinoma; HFD,
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doi: 10.1210/er.2018-00134 https://academic.oup.com/edrv 989

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