COMPLEX LIPID METABOLISM

Phospholipids are:
– major constituents of all cell membranes
– components of bile
– anchor some proteins in membranes
PHOSPHOLIPIDS

– signal mediators
– components of lung surfactant
– components of lipoproteins
 Properties of phospholipids
• Phospholipids are amphipathic molecules
• Head group = alcohol attached via phosphodiester
linkage to either:
– diacylglycerol (glycerophospholipid) or
– sphingosine (sphingophospholipid = sphingomyelin).
PHOSPHOLIPIDS
 Cellular membranes are composed of
phospholipids and sphingolipids
• Glycerophospholipids and sphingolipids spontaneously self-
associate in water to form bilayer vesicles (i.e., closed
membranes)
• Bilayers are permeability barriers that enclose cells and cell
organelles, and “dissolve” intrinsic membrane proteins
PHOSPHOLIPIDS
 Types of phospholipids

• The simplest glycerophospholipid is

phosphatidic acid (PA)
• It consists of glycerol, phosphate, and 2 fatty
acyl chains in ester linkages
PHOSPHOLIPIDS
 Types of phospholipids

Other glycero-
phospholipids
derived from PA
include:
PHOSPHOLIPIDS
 Cardiolipin is found in mitochondrial membranes
PHOSPHOLIPIDS
 Phospholipids are distributed asymmetrically
in the plasma membrane

Outside

Inside
 Plasmalogens

• Plasmalogens have
an ether-linked
hydrocarbon chain at
C-1 of glycerol, instead
PHOSPHOLIPIDS

of ester-linked fatty
acid
 Plasmalogens

• Platelet-activating
factor (PAF) is a
plasmalogen (a
phosphatidalcholine)
with an acetyl group
at C-2 of glycerol
PHOSPHOLIPIDS

• It has potent
physiologic actions
(platelet activation;
inflammatory
responses;
bronchoconstriction)
 Sphingolipids
• Sphingomyelin
contains sphingosine
with a long-chain fatty
acid attached in amide
linkage ( = ceramide)
• Ceramide plus a
PHOSPHOLIPIDS

phosphocholine group
constitutes a
sphingomyelin
• Ceramide is also the
core component of
glycosphingolipids
 Sphingomyelin

• Sphingomyelin is present in plasma

membranes and in lipoproteins
• It is very abundant in myelin
PHOSPHOLIPIDS

• Sphingomyelin is abundant in
specialized plasma membrane
microdomains called lipid rafts
 Lipid rafts
• Lipid rafts are specialized microdomains in the plasma
membrane that are rich in sphingomyelin and cholesterol
• GPI-linked proteins accumulate in lipid rafts
• Lipid rafts appear to function in signaling
 Phospholipid synthesis

• Recall synthesis of PA as an
intermediate of TG synthesis
PHOSPHOLIPIDS

• It involves glycerol-P and two

fatty acyl CoA molecules
 Phospholipid synthesis
• Glycerophospholipid synthesis involves activated
intermediates:
– CDP-alcohol + diacylglycerol or
– CDP-diacylglycerol + alcohol
• Synthesis occurs in the ER of almost all cells
PHOSPHOLIPIDS
 Synthesis of PC
• Choline can be made from ethanolamine by transfer
of 3 methyl groups from S-adenosyl-methionine
• Choline is an essential nutrient
• De novo synthesis of PC from PS involves a
decarboxylation to give PE followed by three
PHOSPHOLIPIDS

methylation steps
 Synthesis of PS & PI

• PS is made by a base exchange reaction:

PE + serine PS + ethanolamine

• PI is synthesized from CDP-diacylglycerol and

myoinositol
PHOSPHOLIPIDS

• PI often has arachidonate in the C-2 glycerol position

 Roles of phosphatidylinositol - I

• PI can provide arachidonate for

eicosanoid synthesis
PHOSPHOLIPIDS
 Roles of phosphatidylinositol - II
• Phosphatidylinositol 4,5-bisphosphate (PIP2) participates in
hormonal signal transduction via activated phospholipase C
formation of inositol-P3 and diacylglycerol, followed by
mobilization of Ca+2 and activation of protein kinase C
PHOSPHOLIPIDS
 Roles of phosphatidylinositol - III
• PI anchors some enzymes to the plasma membrane through a
glycan chain
• Examples include alkaline phosphatase and acetylcholine
esterase
PHOSPHOLIPIDS
 Synthesis of sphingomyelin

• Sphingomyelin is made from:

– palmitoyl CoA + serine
sphingosine
– sphingosine + FA CoA
ceramide
PHOSPHOLIPIDS

– ceramide + CDP-choline
sphingomyelin
• FA are commonly 18:0, 24:0, and 24:1
(15)
 Phospholipid degradation
• Glycerophospholipid degradation occurs by phospholipases present
in tissues (membrane bound or free), pancreatic juice, and venoms
• Phospholipases are specific for ester bonds in the glycero-
phospholipids: phospholipases A1, A2, C, and D
PHOSPHOLIPIDS
 Phospholipases

• Phospholipases A1 and A2 are also

important in the remodeling of phospholipids
• FA CoA is then used in reesterification, e.g.,
to form the dipalmitoylphosphatidylcholine
PHOSPHOLIPIDS

found in lung surfactant or arachidonic acid in

PI
 Sphingomyelin degradation

• Sphingomyelin is degraded
in lysosomes by
sphingomyelinase to give
ceramide,
• and ceramidase to give
PHOSPHOLIPIDS

sphingosine
• Niemann-Pick disease is
due to sphingomyelinase
deficiency
 Glycolipids
• Glycolipids are derivatives of ceramides and sphingosine with
carbohydrate directly attached to ceramide
• In contrast to sphingomyelin they do not have a phosphocholine
group
• Glycolipids are essential components of cell plasma membranes
(outer leaflet), but are most abundant in nervous tissues
GLYCOLIPIDS

Outside

Inside
 Roles of glycolipids

• Glycolipids have important roles in cell

interactions, growth, and development
• They are very antigenic (e.g., blood
group antigens);
• act as surface receptors for some toxins
GLYCOLIPIDS

and viruses;
• and undergo major changes during cell
transformation
 Glycolipid structure — cerebrosides
• The carbohydrate component is linked by an O-
glycosidic bond to ceramide
• Cerebrosides contain a single sugar (Glu or Gal) or
few sugars; they are abundant in brain and myelin
GLYCOLIPIDS
 Glycolipid structure — gangliosides
• Gangliosides are acidic glycosphingolipids
• They contain oligosaccharides with terminal, charged
N-acetyl neuraminic acids (NANA)
• Depending on the number of NANA sugars,
gangliosides are designated M, D, T, Q (e.g., GM)
GLYCOLIPIDS

Ganglioside GM2
 Glycolipid synthesis
• Synthesis of glycosphingolipids takes place in the
ER and Golgi by the sequential addition of sugars by
specific glycosyltransferases
• The sugars are activated: UDP-Glu, UDP-Gal, CMP-
NANA
• Sulfate groups are added last by a sulfotransferase
using PAPS (3'-phosphoadenosine-5'-phosphosulfate)
GLYCOLIPIDS
 Glycolipid degradation

• Degradation of glycosphingolipids occurs

in lysosomes after endocytosis of
membrane portions
• A series of acid hydrolases participate in
GLYCOLIPIDS

the degradation
• Degradation is sequential in the order:
last on, first off
 Glycolipid degradation

• Sphingolipidoses result from

deficiencies of specific degradative
enzymes
• They are diagnosed by accumulation of
GLYCOLIPIDS

specific sphingolipid, enzyme activity

measurements, and histologic
examination of affected tissue
 Some
sphingolipidoses
GLYCOLIPIDS
GLYCOLIPIDS

Fabrazyme® = α-galactosidase A
 Eicosanoids

• Eicosanoids are specialized FA

• They include prostaglandins (PG),
thromboxanes (TX), and leukotrienes (LT)
• Eicosanoids have strong hormone-like actions
in the tissues where they are produced
EICOSANOIDS

• Eicosanoids are not stored and are very

unstable
 Eicosanoid synthesis
• Dietary linoleic acid is the precursor. It is elongated and further
desaturated to 20-carbon, 3, 4, or 5 double bond FAs
• Arachidonate, 20:4 (5, 8, 11, 14), is the precursor of many
eicosanoids
• Arachidonate is normally part of membrane phospholipids
(especially phosphatidylinositol).
• Arachidonate is released by a specialized phospholipase A2
EICOSANOIDS
 Synthesis of prostaglandins from
arachidonate

• The free arachidonic acid is

oxidized and cyclized in the ER
by endoperoxide synthase
( = PGH2 synthase)
• This enzyme has two activities
– cyclooxygenase (COX) and
peroxidase
EICOSANOIDS

• Initially yields PGH2

• Subsequent steps lead to
thromboxane A2 and various
prostaglandins
 Synthesis of leukotrienes from arachidonate

• Leukotrienes are
produced from
arachidonic acid via
a different enzyme:
lipoxygenase
EICOSANOIDS
EICOSANOIDS
 Biological actions of eicosanoids

• Biologic actions of eicosanoids are

diverse in various organs:
– vasodilation, constriction, platelet
aggregation, inhibition of platelet
aggregation, contraction of smooth muscle,
EICOSANOIDS

chemotaxis of leukocytes, release of

lysosomal enzymes

• Excess production symptoms: pain,

inflammation, fever, nausea, vomiting
 Some major polyunsaturated fatty acids

Name Structure Type Significance

Linoleate 18:2(9,12) ω-6 Essential FA
Linolenate 18:3(9,12,15) ω-3 Essential FA
Arachidonate 20:4(5,8,11,14) ω-6 Prostaglandin
EICOSANOIDS

precursor
 Metabolism of linoleate versus linolenate into
polyunsaturated fatty acids (PUFAs):

Linoleate (18:2) (ω-6)

arachidonate (AA) (20:4) (ω-6)

Linolenate (18:3)(ω-3)
eicosapentanoic acid (EPA) (20:5) (ω-3)
EICOSANOIDS

and
docosahexanoic acid (DHA) (22:6) (ω-3)
 Omega-3 fatty acids

• EPA & DHA are precursors for different

eicosanoids than arachidonate
• When we were evolving, dietary ratio of
ω-6 FA (linoleate) to ω-3 FA (linolenate)
was about 1:1 to 2:1
EICOSANOIDS

• Currently it is about 10:1 to 20:1 in

Western diets
• Fish oils have high content of ω-3 FA
 Inhibitors of prostaglandin synthesis
• Corticosteroids (e.g., cortisol) inhibit at the level
of phospholipase A2
• Antiinflammatory drugs (NSAIDS) like
indomethacin & ibuprofen reversibly inhibit COX
• Aspirin irreversibly inactivates COX
EICOSANOIDS
 Cyclooxygenase

• There are at least two isozymes of PGH2 Synthase

(COX-1 and COX-2)
• COX-1 is constitutively expressed at low levels in
many cell types
EICOSANOIDS

• Specifically, COX-1 is known to be essential for

maintaining the integrity of the gastrointestinal
epithelium.
 Cyclooxygenase

• COX-2 expression is stimulated by growth factors,

cytokines, and endotoxin
• COX-2 levels increase in inflammatory disease states
such as arthritis and cancer
• Up-regulation of COX-2 is responsible for the
EICOSANOIDS

increased formation of prostaglandins associated with

inflammation
 Next generation NSAIDs

• Older NSAIDs inhibit both inhibit both COX-1 &

COX-2:
– acetylsalicylate (Aspirin®, Anacin®, etc.)
– ibuprofen (Motrin IB®, Advil®, etc.)
EICOSANOIDS

• Newer generation drugs are specific COX-2

inhibitors:
– Celebrex®
– Vioxx®