Beruflich Dokumente
Kultur Dokumente
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)
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
··
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 TD ().
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 EA-Pbx in the was concluded that the human FGF gene was the
NIHT 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
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 (, , ).
962 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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GSKb 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
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].
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
964 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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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
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
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
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
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(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
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
968 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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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
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
970 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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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
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 CYPA 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 CYPA in the liver
(, –). Further studies have highlighted the
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
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 /pRSK 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/pSK, allowing (, ), as well as CYPA 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
974 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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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
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
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deterioration of glucometabolic status (). Patients particular with conjugated CA), as well as with disease
with TD 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
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
978 Somm and Jornayvaz FGF15/19 From Mice to Humans Endocrine Reviews, December 2018, 39(6):960–989
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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- TD (). 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 TD (). 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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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
treatment paradigms. Oncotarget. 2014;5(9): FGFR4 and bKlotho in patients with thyroid cancer. University Hospitals, University of Geneva Medical School,
2349–2354. Cytokine. 2018;105:32–36. Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
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