Lecture 19

Lipid Metabolism - IV
Metabolism of cholesterol and lipoproteins

Dr. S. Annie Jeyachristy

Lecturer in Biochemistry
Faculty of Medicine
AIMST University
 OBJECTIVES
To provide an overview of
the biosynthesis of cholesterol (in detail up to the level of mevalonate
and only a brief description thereon).
regulation of cholesterol synthesis
the catabolism and excretion of cholesterol
the classification and importance of lipoproteins,
the exogenous and endogenous pathways for transport of lipids
disorders of lipid transport
 CHOLESTEROL

Cholesterol, animal steroid is present in tissues and in plasma lipoproteins either as

free cholesterol or, combined with a long-chain free fatty acid, as cholesteryl ester.
It is synthesized in many tissues from acetyl-CoA and is eliminated from the body in
the bile as cholesterol or bile salts.
Cholesterol is the precursor of all other steroids, such as sex hormones, bile acids,
and vitamin D.
It occurs in foods of animal origin such as egg yolk, meat, liver, and brain.
A little more than half the cholesterol of the body arises by synthesis (about 700
mg/dL), and the remainder is provided by the average diet. The liver accounts for
10% of total synthesis in humans, the intestine for about another 10%.
essential structural component of mammalian cell membranes, where it is required
to establish proper membrane permeability and fluidity.
 FUNCTIONS OF CHOLESTEROL

Cell membranes – membrane fluidity

Nerve conduction – poor conductor, insulates nerve fibre
Bile salts and acids – fat digestion and absorption
Steroid hormones – glucocorticoids, androgens, estrogens
Vitamin D3
Esterification – LCAT – regulation of cholesterol level
 Structure of free cholesterol

Perhydrocyclopentano-phenanthrene nucleus
A, B, C – cyclohexane ring (phenanthrene arrangement), D- cyclopentane ring

Total 27 carbon atoms

Steroids with 8-10 carbon atoms in the side chain at C-17 & a hydroxyl group at C3 are
called sterols.
Double bond between carbon atoms 5 and 6
 Biosynthesis of cholesterol
From 2 carbons to 27 carbons
Synthesized by virtually all cells in humans
Largely in liver, intestine, adrenal cortex, reproductive tissues including ovaries,
testes & placenta
Site of synthesis: Cytosol with enzymes in both cytosol & endoplasmic reticulum
Starting substance: Acetyl CoA
Requires NADPH from HMP pathway
Stages in the synthesis of cholesterol
I. Acetyl-CoA forms HMG-CoA and mevalonate.
II. Mevalonate forms active isoprenoid units.
III. Six isoprenoid units form squalene.
IV. Squalene is converted to lanosterol.
V. Lanosterol is converted to cholesterol.
 Overview of cholesterol biosynthesis

Acetyl CoA (C2) Mevalonate (C6)

Isoprenyl pyrophosphates (C5, C10, C15)

Squalene (C30) Lanosterol (C30)

Cholesterol (C27)
I. Acetyl CoA to Mevalonate
A. B. C.

Acetoacetyl Acetyl CoA

CoA
synthase

HMGCoA reductase-embedded in the

ER, is the rate-limiting enzyme of Rate limiting step
cholesterol biosynthesis
 6C

Kinase

II. Mevalonate to 2
Phosphomevalonate
Activated Isoprenes
Kinase

Kinase

6C

Decarboxylase

5C

Isomerase

5C
 III. Condensation of
Transferase
Isoprenes to form Squalene

10C Head to tail attachment of

isoprenes to form Geranyl
pyrophosphate
Transferase
Head to tail condensation of
Geranyl pyrophosphate and
15C isopentenylpyrophosphate to
form Farnesyl pyrophosphate
Head to head fusion of two
Squalene synthase
Farnesyl pyrophosphate to form
squalene
30C

Fig.6
IV & V. Conversion of squalene to lanosterol and then to
cholesterol

30C

Squalene monooxygenase adds oxygen to form an epoxide

Unsaturated carbons (double bonds) are aligned to allow cyclization and
formation of lanosterol
Cholesterol is synthesized from lanosterol (lanosterol (30C)→zymosterol
(27C) →desmosterol(27C) →cholesterol )after several reactions
 Regulation of cholesterol biosynthesis
HMG CoA reductase is the rate-limiting enzyme in cholesterol synthesis. Feed back
regulation by cholesterol. The amount of dietary cholesterol determines cholesterol
synthesis.
Hormonal regulation: Short term regulation is by covalent modification of the
enzyme. Glucagon via cyclic AMP cascade favours formation of inactive
(phosphorylated) form of HMG CoA reductase. Hence, synthesis of cholesterol
decreases. Glucagon and cortisol decrease its activity.
In contrast, insulin and thyroxine promotes formation of active form of enzyme →
increases synthesis of cholesterol.
Long term regulation involves suppression of transcription of the gene for HMG
CoA reductase synthesis by cholesterol.
Inhibition by drugs: Cholesterol lowering drugs (statin drugs) like Simvastatin,
Lovastatin, Mevastatin (Zocor, Lipitor) are reversible, competitive inhibitors of
HMG CoA reductase. Effective at lowering cholesterol in patients with
hypercholesterolemia
Policosanol, extract from sugar cane wax, acts like the statin drugs i.e. inhibit HMG
CoA reductase
 Cholesterol and Bile acid/salt metabolism

Cholesterol is not degraded to CO2 and H2O coz of its ring

structure
Synthesis of bile acids is the predominant mechanism by which
excess cholesterol is eliminated from the body-excretory form of
cholesterol
Occurs in liver
Bile acid/salts involved in dietary lipid digestion as emulsifiers
Cholestyramine, a non-absorbable ionic resin binds bile salts →
increase the conversion of cholesterol to bile acids and excreted →
treatment to lower cholesterol.
Bile acids/salts – Biological detergents
Bile acids are synthesized from cholesterol and is major
metabolic fate of cholesterol.
Bile acids are synthesized and secreted by the liver and
conjugated with glycine or taurine to form bile salts before
leaving the liver.
Bile salts are stored in gallbladder and passed through the bile
duct into the intestine.
Most of bile salts secreted in upper intestine is absorbed in the
lower small intestine and returned to liver for reuse via the
portal blood – called enterohepatic circulation.
Synthesis of bile acid
Primary bile acids
chenodeoxycholic acid (45%) and Types of Bile
cholic acid (31%) acids/salts
Secondary bile acids
Lithocholic acid and  The carboxyl group of primary
Deoxycholic acids bile acids is conjugated with
Tertiary bile acids glycine or taurine to yield
Ursodeoxycholic acid glycocholic acid and
taurocholic acid which are
called as bile salts.
Bile salts
 Secondary bile acids - formed
glycochenodeoxycholic acid
by the action of intestinal
glycocholic acid bacterial enzyme 7-alpha
glycolithocholic acid dehydroxylase.
glycodeoxycholic acids
taurochenodeoxycholic acid
taurocholic acid
taurolithocholic acid
taurodeoxycholic acids
 Role of bile salts in fat digestion

• Bile salt molecule has both hydrophobic and hydrophilic surfaces

(amphipathic).
• Bile salts able to orient at an oil-water interface, with the
hydrophobic surface in contact with the a polar phase and the
hydrophilic surface in contact with the aqueous phase.
• Detergent action emulsifies lipids and yields micelles hence
allowing attack by water-soluble enzymes.
• Most of the digestion carried out by pancreatic lipase in water-oil
interface.
 Lipoproteins

Lipoproteins are spherical macromolecular complexes of lipids &

specific proteins (apolipoproteins /apoproteins)
The density of lipoproteins is inversely proportional to
triacylglycerol content.
As the density increases both the size and diameter of the particle
decreases.
Functions of lipoproteins:
To keep their component lipids soluble as they transport them
in plasma
To provide an efficient mechanism for transporting their lipid
contents
 Lipoprotein Structure

Lipoproteins-consist of a
lipid core containing non-
protein non polar,
triacylglycerol and
cholesterol ester
surrounded by a single layer
of phospholipids and free
cholesterol and apoprotein
 Classification of Lipoproteins
Chylomicrons
VLDL (very low density lipoproteins)
IDL & LDL (intermediate & low density lipoproteins)
HDL (high density lipoproteins)
 Composition, size, density and transport functions of Plasma
Lipoproteins
Lipoproteins Synthesized in Functions
Chylomicrons intestine transport dietary triacylglycerols &
cholesterol via lymphatics and blood-stream
to tissues.
Chylomicron remnant transport of dietary cholesterol to the liver
VLDL Liver transport of endogenous triacylglycerols &
cholesterol from liver to tissues.
LDL Plasma VLDL transport of endogenous cholesterol to tissues.

HDL Liver and small reverse transport of cholesterol to the liver.

intestine

Composed of hydrophobic lipid core with TAG & cholesteryl esters sorrounded
by amphipathic apoproteins, phospholipids & nonesterified cholesterol
Chylomicrons: lowest in density but largest in size, with highest percentage of
lipids & smallest percentage of protein
VLDL & LDL are successively denser with higher ratios of protein to lipid
HDL is the densest
 Apolipoproteins
Apoprotei Synthesized in Component of Functions
n
Apo-A-I Intestine; liver HDL-2 Activation of LCAT; ligand for HDL
receptor
Apo-A-II Intestine; Liver HDL-3 Inhibitor of LCAT; stimulates hepatic
lipase
Apo-B- Liver LDL; VLDL Binds LDL receptor
100
Apo-B-48 Intestine Chylomicrons 48% size of B-100
Apo-C-I Liver Chylomicrons; VLDL Activation of LCAT
Apo-C-II Liver Chylomicrons; VLDL Activates extrahepatic lipoprotein
lipase in vessel walls; clearance of
TAG from chylomicrons and VLDL

Apo-C-III Liver Chylomicrons; VLDL Inhibits lipoprotein lipase; anti-

atherogenic
Apo-D Liver HDL-3 Lipid transfer protein
Apo-E Liver LDL; VLDL; Chylomicrons Arginine rich; ligand for hepatic
uptake
Chylomicron Metabolism
 Chylomicron Metabolism –Key Features
Adipose tissue and skeletal muscle, half life- 1 hour
Cholesterol absorbed from bile salt micelles into intestinal epithelial cells and
cholesterol synthesized by cells is packaged in chylomicrons - Apolipoproteins &
lipids are assembled to form nascent chylomicrons.
Nascent chylomicrons enter the bloodstream.
Interaction with HDL particles leads to apoprotein gain –apo C-II & apo E.
Apo C-II on chylomicron activates lipoprotein lipase (lpl) and hydrolysis of core
TAG begins- FFA & glycerol released
Chylomicron continues to shrink until TAG is almost totally removed and the
remnant particle detaches from LPL
Apo CII is returned back to HDL
Chylomicron remnant is removed by the liver using apo B48
VLDL Metabolism
 VLDL Metabolism – Key Features
half-life 1-3 hrs
Nascent VLDL are secreted into the bloodstream from the liver
containing apo B-100
Interaction with HDL particles leads to gain of apo C-II & apo E
Apo C-II on VLDL activates lipoprotein lipase and hydrolysis of
core TAG begins.
VLDL continues to shrink until TAG is almost totally removed and
the VLDL remnant particle detaches from LPL as IDL
Surface components C-II & E is returned to HDL , but apo B-100 is
retained to form LDL.
Following lipolysis, there is exchange of TAG and CE between
VLDL remnants/IDL and HDL mediated by Cholesteryl Ester
Transfer Protein (CETP).
 LDL Metabolism – Key Features
Half life – 2 days
LDL produced from IDL is taken up by
the liver and extrahepatic tissues, which
contains LDL receptors.
Contains only apo-B100
LDL receptors, present in all cells but
abundant in hepatic cells, located in
clathrin-coated pits, bind LDL and
brings into the cell by endocytosis
Uptake and lysosomal digestion of
LDL by extrahepatic cells results in
release of cholesterol
Phagocytic macrophages have
nonspecific receptors which binds with
oxidatively modified LDL
LCAT
and amino acids from When macrophages takes up, it is filled
apoproteins
Cholesteryl ester with foam cells – accumulation leads to
plaque formation in blood vessels.
 HDL Metabolism
HDL cholesterol: good cholesterol
Discoidal nascent HDL secreted by liver and small intestine containing ApoA-1,
apo-C-II and apo-E
Apo-E serves as a recognition factor for the cell surface receptors.
Apo A-I activates Lecithin cholesteryl acyl transferase (LCAT).
LCAT converts the cholesterol to cholesteryl esters. This causes accumulation of
CE and HDL now becomes spherical in shape and called as HDL3.
HDL3 transfers CE to VLDL in exchange of TAG and this mediated by
Cholesteryl ester transfer protein (CETP) from VLDL
HDL now gets converted to HDL2 which contains CE, PL, TAG, and LCAT
along with Apo A-II.
HDL2 is small in size.
By the action of Lipoprotein lipase (LPL), C and PL are released and hydrolyzed
in liver.
 Centripetal Transport of Cholesterol by
HDL (Reverse cholesterol transport)

Since HDL removes cholesterol from cells high levels of

HDL is inversely related to risk of atherosclerosis
 Disorders of plasma lipoprotein metabolism

Hyperlipoproteinemia
Hypolipoproteinemia

The study of these disorders is important because they lead to a number of other
disorders:
- heart disease,
- dermatological manifestation [ xanthomas]
- pancreatitis

Xanthomas of the eyelid

-generally associated with
hypercholesterolemia
Eruptive Xanthomas
-generally associated with
hypertriglyceridemia
 Hyperlipoproteinemia - Frederickson’s classification
1. Type I: Hyperchylomicronemia (LPL deficiency)
2. Type II: Hypercholesterolemia (LDL receptor deficiency)
3. Type III: Dysbetalipoproteinemia (Abnormal apo-E)
4. Type IV: Familial endogenous type (increased production of
VLDL)
5. Type V: Increased VLDL & chylomicrons due to secondary
causes

Type I, IV and V --- Hypertriglyceridemia

Type II A -- Hypercholesterolemia
Type IIB and Type III – Both Hypertriglyceridemia and Hypercholesterolemia
Type Metabolic defect Affected Plasma cholesterol Plasma TAG
lipoprotein
Type I Deficiency of chylomicron Normal Highly
lipoprotein lipase elevated
Type II A Defective LDL LDL Highly elevated Normal
receptors;
overproduction of
Apo B
Type II B Over production of LDL and VLDL Highly elevated Elevated
Apo B 100, apo
CII
Type III Abnormality in VLDL and Increased Elevated
Apo E, apo CII↑ chylomicrons
Type IV Overproduction of VLDL Increased or Highly
VLDL, apo CII↑ normal Elevated
Type V Unknown VLDL, Normal Highly
chylomicrons elevated
 Lipoproteins (lp)

1. Largest lp chylomicrons
2. Most protein-rich lp chylomicron remnants
3. Transports endogenous TAGs VLDL
4. Facilitates reverse cholesterol transport IDL
5. Transports dietary TAG LDL
6. Inverse risk for atherosclerosis HDL
7. Major apoprotein of Chylos Apo B-48
8. Major apoprotein of LDL Apo B-100
9. Transfers lipids between HDL and VLDL LPL
10. Hydrolyzes TAGs in VLDL CETP
 LEARNING OUTCOMES
To provide an overview of
Describe the steps involved in de novo synthesis of cholesterol and
explain how it is regulated.
Discuss the role of statin drugs in inhibiting cholesterol synthesis.
Explain how cholesterol is degraded and excreted in bile.
Describe the structure and classification of lipoproteins.
Discuss the importance of lipoproteins.
Distinguish the exogenous and endogenous pathways for the transport
of lipids.
Discuss the disorders associated with lipid metabolism and transport.