LIPID METABOLISM

Dolores V. Viliran, M.D.

Professor of Biochemistry & Nutrition
FEU-NRMF,INSTITUTE OF MEDICINE
 Overview
Digestive lipid metabolism

De Novo Synthesis of Fatty acid

Synthesis of Triacylglycerols

Mobilization of Stored Fats and Oxidation of Fatty

acids

Synthesis of Ketone bodies

 Overview (cont.)
Phospholipid Metabolism

Glycolipid Metabolism

Metabolism of Prostaglandins and

Related compounds

Cholesterol Metabolism

Blood Lipoproteins
 Digestive Lipid Metabolism
Emulsification of Dietary lipids in the small intestines

- emulsification inc. the surface area

lipase activity
- detergent property of bile salt and
peristalsis
> Pancreatic activity

A. Hormonal Control of Lipid Digestion

1. CCK/pancreozymin
 1. Triacyglycerol hydrolysis
- TAG are acted upon by pancreatic
lipase and removes FA at carbon 1 and 3
- products = 2-monoacylglycerol +
FA
2. Cholesteryl ester degradation
- Cholesterol esterase
- Products: Cholesterol + FA
Absorption of Lipids by intestinal mucosal
cells
- FFA, free cholesterol, 2-monoacylglycerol
and lysophospholipid together with bile
salts from mixed micelles which is absorbed
at the brush border membrane of SI
- short and medium chain FA are directly
absorbed
Reverse Cholesterol Transport via
Peripheral HDL
Blood Liver
Tissues

Excess
Cholesterol
Bile
Cholesterol Catabolism into Bile Salts
Cholesterol Cholate

OH

COO -

HO
HO
Cholesterol OH
7-hydroxylase
 Bile Salts
Breakdown products of cholesterol

Amphipathic molecules

Function to transport cholesterol in the digestive

system
 Structure of Biliary and Intestinal
Micelles
Cholesterol

Bile Salt

Phospholipid
 Functions of Micelles
Transport cholesterol from the liver into the
intestine via the biliary tree

Participate in fat digestion and absorption

 Biliary Lipid Secretion
Blood Hepatocyte Bile

Sinusoidal Membrane
ABCG5/G8
Cholesterol

ABCB4
Phospholipid

ABCB11 Bile Salt

Canalicular Membrane
 Biliary Lipids
Lipid Class Daily Secretion (g)

Bile salts 24

Phospholipids 11

Cholesterol 2
Biliary Lipid Transport
Liver

Duodenum
Biliary
Transport
and
Storage Jejunum

Ileum

Colon
 Fat Digestion
Liver

Duodenum
Biliary
Transport
and
Storage Jejunum

Ileum

Colon
 Fat Digestion

I
II IIII
I II
Dietary Triglycerides Phospholipids
Cholesterol

Fatty Acids + Fatty Acids +

Monoglycerides Lysophospholipid
II
I
I
II II II
I I II I
I
 Fat Absorption
Liver

Duodenum
Biliary
Transport
and
Storage Jejunum

Ileum

Colon
 Cholesterol Absorption

Intestinal
Lymph Enterocyte Lumen

Cholesterol

ACAT

Cholesteryl
Ester
 Triglyceride Absorption

Lymph Enterocyte Intestinal

Lumen

2 Fatty Acid
+
Monoglyceride

DGAT

Triglyceride
 Phospholipid Absorption

Intestinal
Lymph Enterocyte Lumen

Fatty Acid
+
Lysophospholipid

Phospholipid
 Chylomicron Formation

Intestinal
Lymph Enterocyte Lumen

Phospholipid

Triglyceride

With
apoB48 Cholesteryl
Ester
Figure 23.1 Absorption and transport of dietary fat.

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Lipogenesis
 Lipogenesis

Defined as biosynthesis of fatty acid

There are three types of lipogenic pathways based on cellular

localization:

1. Extramitochondrial cytosol
2. Microsomal smooth endoplasmic reticulum
3. Mitochondrial mitochondrion

General principle: Add 2 carbon atoms per cycle

Extramitochondrial Mitochondrial Microsomal
De novo Elongation Elongation
(Type) (Type)
Acetyl CoA Medium to long chain fatty acids
(Substrate) (Substrates)

Palmitic acid Longer chain fatty acids

(End-product) (End-products)

Malonyl CoA Acetyl CoA Malonyl CoA

(Donor of 2 C) (Donor of 2 C)

Uses acyl carrier Use coenzyme A to anchor

protein (ACP) fatty acid

All involve reduction-dehydration-reduction

 De Novo Synthesis of Fatty Acids

Production of Acetyl CoA

Carboxylation of Acetyl CoA
Fatty acid synthase: a multienzyme complex
AcetylCoA-ACP transacylase
MalonylCoA-ACP transacylase
-ketoacyl-ACO synthase
Palmitoyl thioesterase
 De Novo Synthesis of Fatty Acids
Production of Acetyl CoA Translocation of mitochondrial
citrate to cytosol
Conversion of citrate to acetyl C
oxaloacetate by citrate lyase
Requirement: Inc. ATP and Citra
 Extramitochondrial Lipogenesis

Glucose is the source of acetyl CoA

Glucose
Glycolysis (cytosol)
Pyruvic acid

Pyruvate DH (mitochondria)
Acetyl CoA
 Extramitochondrial Lipogenesis
How did acetyl CoA get into the cytosol?
Acetyl CoA + Oxaloacetate

Citrate Mitochondrion

*****************************************
Citrate Cytosol
citrate lyase
Acetyl CoA + Oxaloacetate
 Figure 23.13 Transport of acetyl units from the mitochondrion to the cytoplasm. The inner
mitochondrial membrane has carriers for citrate, pyruvate, and malate but not for acetyl-CoA
and oxaloacetate.
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 Pathway for the movement of acetyl-CoA units from within the
mitochondrion to the cytoplasm for use in lipid and cholesterol
biosynthesis. Note that the cytoplasmic malic enzyme catalyzed reaction
generates NADPH which can be used for reductive biosynthetic reactions
such as those of fatty acid and cholesterol synthesis.
 Extramitochondrial Lipogenesis
Rx 1 CH3COSCoA Acetyl CoA

CO2 acetyl CoA carboxylase

+ biotin

COOH Malonyl CoA

CH2COSCoA
Note: Rate-limiting step
 Extramitochondrial Lipogenesis

The formation of malonyl CoA is a two-step reaction:

Rxn 1 ATP + *HCO3- + Enz-biotin

Enz-biotin-*COO- + ADP + Pi

Rxn 2 Acetyl CoA Acetyl CoA carboxylase

Malonyl CoA + Enz-biotin

 Extramitochondrial Lipogenesis
Rx 2 COOH Malonyl CoA
CH2COSCoA

ACP-SH Malonyl transacylase

(Fatty acyl synthase cplx)
CoASH
COOH Malonyl-ACP
CH2COS-ACP
Fatty Acid Synthase
Enzyme Complex
Fatty Acid Synthase Enzyme Complex
 Extramitochondrial Lipogenesis

Rx 3. 1st Condensation reaction

COOH Malonyl-ACP
CH2COS-ACP

acetyl CoA acetyl transacylase,

ketoacyl synthase
CO2
CH3CO-CH2-COS-ACP Acetoacetyl-ACP
 Extramitochondrial Lipogenesis
Rx 4. Reduction

CH3CO-CH2-COS-ACP Acetoacetyl-ACP
NADPH + H+ ketoacyl reductase

NADP
CH3 CHOH-CH2-COS-ACP
B-hydroxyacyl-ACP
 Extramitochondrial Lipogenesis

Rx 5. Dehydration

CH3CHOH-CH2-COS-ACP B-hydroxyacyl-
ACP
H2O hydratase

CH3 -CH=CH-COS-ACP &,B-unsaturated

acyl-ACP
 Extramitochondrial Lipogenesis

Rx 6. Reduction

CH3-CH=CH-COS-ACP&,B-unsaturated acyl-ACP
NADPH + H+
Enoyl reductase
NADP
CH3-CH2-CH2-COS-ACP Butyryl-ACP
(Acyl-ACP)
 Extramitochondrial Lipogenesis

Sources of NADPH
1. HMP shunt
2. Malic enzyme rxn
Citrate oxaloacetate
Malate
NADP Malic enzyme (NADP malate DH)

NADPH CO2
Pyruvate
 Extramitochondrial Lipogenesis
Rx 6. Another round of rxn going back to rx 3

CH3-CH2-CH2-COS-ACP Butyryl-ACP

Malonyl-ACP malonyl transacylase

CH3-CH2-CH2-CH2-CH2-COS-ACP Acyl-ACP
primer first second
acetyl CoA malonyl malonyl
 Extramitochondrial Lipogenesis

CH3-CH2-CH2-CH2-CH2-COS-ACP Acyl CoA

after cycling steps
3 -6 several times

CH3-(CH2)14-COS-ACP Palmitoyl-ACP

deacylase (thioesterase)
CH3-(CH2)14-COOH Palmitic acid
 Summary of Extramitochondrial Lipogenesis
Takes place in the cytosol
Conversion of acetyl CoA to malonyl CoA is the rate-limiting step or
committed step
Acetyl CoA carboxylase is the rate-limiting or committed enzyme
Biotin is the prosthetic group of acetyl CoA carboxylase
Acetyl CoA carboxylase is inhibited by palmitic acid (negative
feedback mechanism)
Avidin, a protein found in raw egg white, inhibits the committed step
by binding and removing biotin from the reaction
 Regulation of Lipogenesis
A. Regulation of acetyl CoA carboxylase activity
1. Inhibited by palmitic acid and other long-chain fatty
acyl CoA negative feedback inhibition
2. Activated by citrate, an indicator of a plentiful supply of
acetyl CoA, converts the enzyme from the inactive dimer
to an active polymeric form
3. Hormonal regulation
a) Insulin activates the enzyme by promoting its
dephosphorylation
b) Glucagon and epinephrine inactivates the
enzyme by promoting its phosphorylation
via cAMP-dependent protein kinase
 Regulation of lipogenesis
2. Avidin, a protein found in raw egg white, inhibits the
committed step by binding biotin, the prosthetic group of
acetyl CoA carboxylase
3. Nutritional state that favors lipogenesis
a) Well-fed state high carbohydrate diet
b) High intake of sucrose fructose bypasses the
phosphofructokinase control point in glycolysis
4. Nutritional state that depresses lipogenesis
a) restricted caloric intake
b) high fat diet
c) deficiency of insulin, e.g. diabetes mellitus
 Regulation of lipogenesis
5. Induction and repression of enzyme synthesis
a) Insulin stimulates transcription of the gene that codes
for acetyl CoA carboxylase and fatty acid synthase complex
b) Glucagon antagonizes this effect
c) High fat diet containing PUFA inhibits expression of key
enzymes of glycolysis and lipogenesis
6. Other mode of regulation by long-chain fatty acyl CoA
a) It inhibits the mitochondrial tricarboxylate (citrate)
transporter
b) It also inhibits pyruvate dehydrogenase
 De Novo Synthesis of Fatty Acids
Carboxylation of acetyl
CoA to malonyl CoA Carboxylation of AcetylCoA to
Regulators of acetylCoA malonylCoA by AcetylCoA
carboxylase carboxylase
Activators: insulin,Inc. Rate limiting step in fatty acid
CHO intake, fat-free diet synthesis
Inhibitors: malonyl CoA, Coenzyme: Biotin
palmitoyl
CoA,epinephrine,
fasting, high fat diet
Figure 23.14 Regulation of acetyl-CoA carboxylase by allosteric effectors and hormones.
Green arrow, stimulation; red arrow, inhibition. AMP, adenosine monophosphate; cAMP, cyclic AMP.
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 De Novo Synthesis of Fatty Acids
Fatty acid synthase: a
multienzyme complex
Substrate: AcetylCoA and Carbons 15 and 16 of palmitic acid from
MalonylCoA priming acetyl CoA
End Product: Palmitic acid Carbons 1-14 of palmitic acid are
Site: Cytosol derived from 7 malonyl CoA ( 2 carbons
Priming Molecule: Acetyl CoA from malonyl CoA are added 7 times to
Rate-limiting enzyme: Acetyl the priming acetylCoA molecule
CoA carboxylase NADPH + H+ are from HMP-Shunt
Primary enzyme of synthesis:
Fatty acid synthase

1 AcetylCoA + 7 malonylCoA + 14 NADPH+ 14 H

Palmitic acid + 7 CO2 + 6H2O+ Co-A-SH +14 NADP

 Synthesis of Triglycerides
Fatty acids are stored for future use as
triacylglycerols in all cells, but primarily in adipocytes
of adipose tissue
Triacylglycerols constitute molecules of glycerol to
which three fatty acids have been esterified
The fatty acids present in triacylglycerols are
predominantly saturated
 Synthesis of Triglycerides
The major building block for the synthesis of
triacylglycerols, in tissues other than adipose tissue,
is glycerol
Adipocytes lack glycerol kinase, therefore,
dihydroxyacetone phosphate (DHAP), produced
during glycolysis, is the precursor for triacylglycerol
synthesis in adipose tissue
This means that adipocytes must have glucose to
oxidize in order to store fatty acids in the form of
triacylglycerols
 TRIGLYCERIDE SYNTHESIS
The glycerol backbone of triacylglycerols is activated
by phosphorylation at the C-3 position by glycerol
kinase
The utilization of DHAP for the backbone is carried
out through the action of glycerol-3-phosphate
dehydrogenase, a reaction that requires NADH (the
same reaction as that used in the glycerol-phosphate
 TRIGLYCERIDE SYNTHESIS

The fatty acids incorporated into triacylglycerols are

activated to acyl-CoAs through the action of acyl-
CoA synthetases
Two molecules of acyl-CoA are esterified to glycerol-
3-phosphate to yield 1,2-diacylglycerol phosphate
(commonly identified as phosphatidic acid)
 TRIGLYCERIDE SYNTHESIS

The phosphate is then removed, by phosphatidic

acid phosphatase, to yield 1,2-diacylglycerol, the
substrate for addition of the third fatty acid
Intestinal monoacylglycerols, derived from the
hydrolysis of dietary fats, can also serve as
substrates for the synthesis of 1,2-diacylglycerols.
Figure 23.2 The sources of glycerol 3-phosphate for fat synthesis in adipose tissue. After a carbohydrate meal (high insulin), most glycerol phosphate is derived from glucose.
Glyceroneogenesis from pyruvate is the major source during fasting, leading to substantial futile cycling.

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Synthesis of Triacylglycerol
Synthesis of Triacylglycerol
 Triacylglycerol Biosynthesis
Lipids, such as,
triacylglycerols,
phosphoacylglycer
ols, and steroids
are derived from
FA and
metabolites of FA
 Phospholipid Synthesis

Phospholipids can be synthesized by two

mechanisms
1. One utilizes a CDP-activated polar head group for
attachment to the phosphate of phosphatidic acid
2. utilizes CDP-activated 1,2-diacylglycerol and an
inactivated polar head group.
 Biosynthesis of
Phosphoacylglycerols
 PHOSPHATIDYLCHOLINE: LECITHINS
PC: lecithins
They contain primarily palmitic or stearic acid at carbon 1
and primarily oleic, linoleic or linolenic acid at carbon 2
The lecithin dipalmitoyllecithin is a component of lung or
pulmonary surfactant
It contains palmitate at both carbon 1 and 2 of glycerol
and is the major (80%) phospholipid found in the
extracellular lipid layer lining the pulmonary alveoli
 LECITHIN

Choline is activated first by phosphorylation and

then by coupling to CDP prior to attachment to
phosphatidic acid
Another pathway to PC synthesis, involves the
conversion of either PS or PE to PC. The
conversion of PS to PC first requires
decarboxylation of PS to yield PE; this then
undergoes a series of three methylation reactions
utilizing S-adenosylmethionine (SAM) as methyl
group donor
 PHOSPHATIDYLETHANOLAMINE
PE: They contain primarily palmitic or stearic acid
on carbon 1 and a long chain unsaturated fatty
acid (e.g. 18:2, 20:4 and 22:6) on carbon 2
Synthesis of PE can occur by two pathways
The first requires that ethanolamine be activated by
phosphorylation and then by coupling to CDP. The
ethanolamine is then transferred from CDP-
ethanolamine to phosphatidic acid to yield PE
The second involves the decarboxylation of PS.
 PHOSPHATIDYLSERINE
PS:
The pathway for PS synthesis involves an exchange
reaction of serine for ethanolamine in PE and choline in
PC
These exchange occur when PE and PC are in the lipid
bilayer of the a membrane
As indicated PS can serve as a source of PE through a
decarboxylation reaction
 PHOSPHATIDYLINOSITOL
PI:These molecules contain almost exclusively
stearic acid at carbon 1 and arachidonic acid at
carbon 2
These molecules exist in membranes with various levels
of phosphate esterified to the hydroxyls of the inositol
The polyphosphoinositides are important intracellular
transducers of signals emanating from the plasma
membrane.
 PHOSPHATIDYLINOSITOL
The synthesis of PI involves CDP-activated 1,2-
diacylglycerol condensation with myo-inositol. PI
subsequently undergoes a series of
phosphorylations of the hydroxyls of inositol leading
to the production of polyphosphoinositides
One polyphosphoinositide (phosphatidylinositol 4,5-
bisphosphate, PIP2) is a critically important membrane
phospholipid involved in the transmission of signals for
cell growth and differentiation from outside the cell to
inside
 PHOSPHATIDYLGLYCEROLS
PG:These molecules are found in high concentration
in mitochondrial membranes and as components of
pulmonary surfactant
PG is synthesized from CDP-diacylglycerol and glycerol-3-
phosphate
The vital role of PG is to serve as the precursor for the
synthesis of diphosphatidylglycerols (DPGs).
 DIPHOSPHATIDYLGLYCEROL
DPG:These molecules are very acidic, exhibiting a
net charge of -2 at physiological Ph
They are found primarily in the inner mitochondrial
membrane and also as components of pulmonary
surfactant
DPG,also known as cardiolipins are synthesized by the
condensation of CDP-diacylglycerol with PG.
 PHOSPHOLIPID DEGRADATION
Phospholipid degradation results from the action of
phospholipases
The remodeling of acyl groups in phospholipids is the
result of the action of phospholipase A1 and
phospholipase A2.
Sites of the action of phospholipases A1,A2,C,C
 Metabolism of the Sphingolipids

The core of sphingolipids is the long-chain amino

alcohol, sphingosine.
The sphingolipids include sphingomyelins and
glycosphingolipids (cerebrosides, sulfatides,
globosides and gangliosides)
Ceramide ,the molecule present both in
sphingomyelins and glycosphingolipids , derived
from the condensation of serine and palmitoyl-CoA
 Biosynthesis of
Sphingosine/Ceramide
Require starting
materials palmitoyl-
CoA and serine
 Disorder Enzyme Deficiency Accumulating Substance Symptoms
mental retardation,
Tay-Sachs disease Hexosaminidase A GM2 ganglioside blindness, early
mortality

hepatosplenomegaly,
mental retardation in
Gaucher's disease Glucocerebrosidase Glucocerebroside
infantile form, long bone
degeneration

Globotriaosylceramide; also
kidney failure, skin
Fabry's disease -Galactosidase A called ceramide trihexoside
rashes
(CTH)

Niemann-Pick
disease, more info
all types lead to mental
below Sphingomyelinase Sphingomyelin
retardation,
Types A and B see info below LDL-derived cholesterol
hepatosplenomegaly,
Type C1 see info below LDL-derived cholesterol
early fatality potential
Type C2
Type D
 Disorder Enzyme Deficiency Accumulating Substance Symptoms
Krabbe's disease;
mental retardation,
globoid Galactocerebrosidase Galactocerebroside
myelin deficiency
leukodystrophy
same symptoms as Tay-
Sandhoff-Jatzkewitz Hexosaminidase A and
Globoside, GM2 ganglioside Sachs,progresses more
disease B
rapidly
mental retardation,
GM1 ganglioside: b -
GM1 gangliosidosis GM1 ganglioside skeletal abnormalities,
galactosidase
hepatomegaly
Sulfatide lipodosis; mental retardation,
metachromatic Arylsulfatase A Sulfatide metachromasia of
leukodystrophy nerves

cerebral degeneration,
Fucosidosis -L-Fucosidase Pentahexosylfucoglycolipid thickened skin, muscle
spasticity

Farber's hepatosplenomegaly,
Acid ceramidase Ceramide
lipogranulomatosis painful swollen joints
 Metabolism of the Eicosanoids
Prostaglandins (PGs)
thromboxanes (TXs)
leukotrienes (LTs)
Prostanoid Synthesis via the Cyclooxygenase
Pathway
Prostanoids are synthesized by prostaglandin H synthase (PGHS)
PGHS has two separate enzyme activities:
1. cyclooxygenase 2. peroxidase
PGHS has two isoenzymes:
1. PGHS 1 2. PGHS 2
- each having cyclooxygenase and peroxidase activities
Most prostanoids are synthesized from arachidonic acid
Arachidonic acid is released from membrane phospholipid by
phospholipase A2
 Cyclooxygenase: A Suicide Enzyme

Switching off of prostaglandin formation is partly achieved by a

remarkable property of cyclooxygenase that of self-catalyzed
destruction.

Inactivation of prostaglandins, once formed, is rapid.

Due to the action of 15-hydroxyprostaglandin dehydrogenase.

 Two Isoforms of Cyclooxygenase:
COX-1 and COX-2
1. COX-1 is constitutively expressed while COX-2 is made only in response to
inflammatory mediators such as cytokines.
2. Both are inhibited by non-specific NSAIDs such
as aspirin, ibuprofen and mefanamic acid.
3. Major side effects of blocking COX-1 activity are gastritis and GI bleeding
4. Celecoxib and rofecoxib block COX-2 but not
COX-1 activity hence they are called COX-2
specific inhibitors.
5. COX-2 specific inhibitors do not cause gastric
irritation and bleeding.
 Conversion of Arachidonic Acid to
Series 2 Prostaglandins
Membrane phospholipid
phospholipase A2 (-) steroid drugs,
cortisol, betamethasone
Arachidonic acid
2O2 cyclooxygenase (-) aspirin, ibuprofen
indomethacin PGG2
(endoperoxide)
peroxidase
PGH2 (endoperoxide)
Prostaglandin series 2 synthesis
cont.
PGH2
isomerase thromboxane synthase
(-)
PGE2 TXA2 imidazole,
dipyridamole
isomerase
reductase TXB2
PGF2 PGD2
prostacyclin
synthase PGI2 PGF1
 Properties of significant Eicosanoids

Major
Eicosanoid site(s) of Major biological activities
synthesis

inhibits platelet and leukocyte aggregation, decreases T-cell

PGD2 mast cells proliferation and lymphocyte migration and secretion of IL-
1 and IL-2; induces vasodilation and production of cAMP

increases vasodilation and cAMP production, enhancement

of the effects of bradykinin and histamine, induction of
kidney,
uterine contractions and of platelet aggregation,
PGE2 spleen,
maintaining the open passageway of the fetal ductus
heart
arteriosus; decreases T-cell proliferation and lymphocyte
migration and secretion of IL-1 and IL-2
 Major site(s)
Eicosanoid Major biological activities
of synthesis

kidney, increases vasoconstriction, bronchoconstriction and

PGF2a
spleen, heart smooth muscle contraction

precursor to thromboxanes A2 and B2, induction of platelet

PGH2 -
aggregation and vasoconstriction

heart, inhibits platelet and leukocyte aggregation, decreases T-

vascular cell proliferation and lymphocyte migration and secretion of
PGI2
endothelial IL-1 and IL-2; induces vasodilation and production of
cells cAMP

induces platelet aggregation, vasoconstriction, lymphocyte

TXA2 platelets
proliferation and bronchoconstriction
Eicosanoid Major site(s) of synthesis Major biological activities
TXB2 platelets induces vasoconstriction

monocytes, basophils, induces leukocyte chemotaxis and aggregation,

LTB4 neutrophils, eosinophils, vascular permeability, T-cell proliferation and
mast cells, epithelial cells secretion of INF- g, IL-1 and IL-2

monocytes and alveolar

component of SRS-A, induces vasodilation,
macrophages, basophils,
LTC4 vascular permeability and bronchoconstriction
eosinophils, mast cells,
and secretion of INF- g
epithelial cells

monocytes and alveolar predominant component of SRS-A, induces

LTD4 macrophages, eosinophils, vasodilation, vascular permeability and
mast cells, epithelial cells bronchoconstriction and secretion of INF-g

component of SRS-A, induces vasodilation and

LTE4 mast cells and basophils
bronchoconstriction
LipoProteins
Lipoproteins
Figure 25.3 Metabolism of chylomicrons. C, free cholesterol; CE, cholesterol ester; HDL, high-density
lipoprotein; LPL, lipoprotein lipase; PL, phospholipid; TG, triglyceride.

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 Figure 25.4 Metabolism of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). C, free
cholesterol; CE, cholesterol esters; HDL, high-density lipoprotein; HL, hepatic lipase; LPL, Lipoprotein lipase;
PL, phospholipid; TG, triglyceride.
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LIPOPROTEIN METABOLISM
Figure 25.8 Hypothetical model for the formation of a fatty streak. The extracellular lipid deposits of the fatty streak are thought to
induce a fibroproliferative response, leading eventually to the formation of an atheromatous plaque. indicates a scavenger
receptor. HDL, high-density lipoprotein; LDL, low-density lipoprotein.

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Figure 25.9 Relationship between the plasma cholesterol level and death from coronary heart disease (CHD).

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 Figure 25.10 Metabolism of LDL in normal individuals and in patients with homozygous familial hypercholesterolemia. A, Normal: Both liver and
extrahepatic tissues obtain most of their cholesterol from receptor-mediated low-density lipoprotein (LDL) uptake. The LDL-derived cholesterol inhibits
endogenous synthesis at the level of HMG-CoA reductase. indicates a LDL receptor; , a scavenger receptor. HL, hepatic lipase; IDL, intermediate-
density lipoprotein; LPL, lipoprotein lipase; VLDL, very-low-density lipoprotein. B, Familial hypercholesterolemia, homozygous. LDL is redirected from
parenchymal cells in liver and extrahepatic tissues to tissue macrophages, which become foam cells. These foam cells contribute to the formation of
xanthomas, fatty streaks, and atherosclerotic lesions.
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 Figure 25.11 Effects of a bile acid binding resin (cholestyramine) and a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor
(lovastatin) on cholesterol metabolism. A, Normal or hyperlipidemic. indicates a low-density lipoprotein (LDL) receptor. LPL, extrahepatic lipoprotein
lipase; IDL, intermediate-density lipoprotein; VLDL, very-low-density lipoprotein. B, Effect of cholestyramine: Hepatic LDL receptors are up-regulated.
The liver removes an increased amount of LDL to obtain cholesterol for bile acid synthesis. C, Effect of lovastatin: LDL receptors are up-regulated in
all tissues. The cells require an increased amount of LDL cholesterol because they are unable to obtain cholesterol from endogenous synthesis.

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