Cholesterol metabolism

Professor of Medical Biochemistry

Learning objectives

• To enlist the structure, synthesis, and excretion of cholesterol

• To illustrate the steps and regulatory mechanisms of cholesterol

synthesis pathway.

• To define and explain hypercholesterolemia.

• To specifythe importance of cholesterol and other lipids as a risk

factor for coronary heart disease.

• To illustrate the structure of lipoprotein as complex lipids

• To describe classes and separation of lipoprotein.

• To explain the metabolism of chylomicrons, VLDL, LDL and HDL.

Structural component of all cell

membranes, modulating their fluidity

Cholesterol is a precursor of :

Bile acids

Steroid hormones

Vitamin D

Diet

De novo synthesis

Cholesterol synthesized

in extrahepatic tissues

Liver cholesterol

pool

Free cholesterol

In bile

bile salts/acidsSecretion of HDL

and VLDL

• Synthesis occurs in the cytoplasm of all tissues, with

enzymes in both the cytosol and the membrane of the

endoplasmic reticulum.

• liver, intestine, adrenal cortex, and reproductive tissues,

including ovaries, testes, and placenta, make the largest

contributions to the body's cholesterol pool.

Sterol-dependent regulation of gene expression

• increase in insulin favors upregulation of the

expression of the HMG CoA reductase gene.

• Glucagon has the opposite effect.

Simvastatin

Lovastatin

Mevastain

• Because of their

hydrophobicity,

cholesterol and its esters

must be transported in

association with protein

as a component of a

lipoprotein particle or be

solubilized by

phospholipids and bile

salts in the bile

Lipoproteins

Complexes of lipids and proteins

Function

• Keep its lipid component soluble

• transport lipid in plasma

Structure of Lipoproteins

Lipoproteins are composed of

a neutral lipid core

(containing triacylglycerol,

cholesteryl esters)

surrounded by a shell of

amphipathic apolipoproteins,

phospholipid, and

nonesterified cholesterol

Size and density of Lipoprotein

• Chylomicrons

• VLDL

• IDL

• LDL

• HDL

Types andComposition

ofLipoproteins

Chylomicrons

Very low density

Lipoprotein (VLDL)

Low density

Lipoprotein (LDL)

High density

Lipoprotein (HDL)

Chylomicrons are assembled

in intestinal mucosal cells

and carry dietary

triacylglycerol, cholesterol,

fat-soluble vitamins, and

cholesterol esters (plus

additional lipids made in

these cells) to the peripheral

tissues

They are composed

predominantly of triacylglycerol

and their function is to carry this

lipid from the liver to the

peripheral tissues. where, the

triacylglycerol is degraded by

lipoprotein lipase

Release Of VLDL

• VLDLs are secreted directly into the blood

by the liver as nascent VLDL particles

containing apolipoprotein B-100.

• They must obtain apo C II and apo E from

circulating HDL.

• As with chylomicrons, apo C-ll is required

for activation of lipoprotein lipase.

• Surface components, including the C

and E apoproteins, are returned to

HDL, but the particles retain apo B-100

• Finally, triacylglycerols are transferred

from VLDL to HDL in an exchange

reaction that concomitantly transfers

cholesteryl esters from HDL to VLDL.

This exchange is accomplished by

cholesteryl ester transfer protein

• LDL particles contain much less

triacylglycerol than their VLDL

predecessors, and have a high

concentration of cholesterol and

cholesteryl esters

Two modes of uptake of cholesterol into

macrophages

HDL metabolism

HDL particles are secreted directly into

blood from the liver and intestine

Transports Cholesterol from the

Tissues to the Liver

Scavenger of Cholesterol

SR-BI (scavenger receptor, class B, type 2)

• Nascent HDL are disk-shaped particles

containing primarily phospholipid and

apolipoproteins A, C, and E. They are

rapidly converted to spherical particles

as they accumulate cholesterol .

• When cholesterol is taken up by HDL, it is

immediately esterified by the plasma enzyme

phosphatidylcholine:cholesterol acyltransferase

(PCAT, also known as LCAT, in which "L“ lecithin).

• This enzyme is synthesized by the liver.

• PCAT binds to nascent HDLs, and is activated by apo

A1

• PCAT transfers the fatty acid from carbon 2 of

phosphatidyle choline to cholesterol.

• The ring structure of cholesterol cannot be metabolized to

CO2 and H2O in humans.

• Sterol nucleus is eliminated from the body by conversion

to bile acids and bile salts, which are excreted in the feces

• Secretion of cholesterol into the bile, which transports it to

the intestine for elimination.

• Some of the cholesterol in the intestine is modified by

bacteria before excretion to coprostanol and cholestanol.

Together with cholesterol, (neutral Fecal sterols).

• Lipoprotein (a), in large quantities in the plasma, is

associated with an increased risk of coronary heart

disease.

• Nearly identical LDL particle.

• presence of an additional apolipoprotein molecule, apo(a),

that is covalently linked at a single site to apo 100

• Circulating levels of lp(a) are determined by:

Genetics.

Diet

Estrogen decreases both LDL and lp(a).

Cholesterol

+Triglycerides

Lipoproteins

VLDL

HDL LDL

LDH and HDL are forms in

which fat and cholesterol get

transported in the blood

HDLgood

LDLbad

Familial hypercholesterlomia

• Defective LDL receptor function

• Hypercholesterolemia caused by

mutations affecting key proteins in

the LDL receptor

endocytic/recycling pathways

• Prevalence 1 in 500, perhaps 1 in

300 in all ethnicities worldwide.

Gradual deposition of cholesterol in the tissues,

particularly in the endothelial linings of blood

vessels is a potentially life-threatening as it leads to

plaque formation, causing the narrowing of blood

vessels (atherosclerosis) and increased risk of

Atherosclerotic Plaque

• Focal accumulation of smooth muscle cells,

foam cells, cholesterol crystals and lipid under

the endothelium of the artery (within the Tunica

Intima)

• Given time, this plaque can protrude into the

lumen of the vessel reducing blood flow

• Often develops at branch points or curves within

the vasculature blood is slowed and/or

turbulent

39

Effect of Atheroma

• As the heart senses a decrease in O2, there is

attempted compensation:

– Increase Heart Rate

– Increase Blood Pressure

– Aggravation/Worsening of the atheroma

• When 70% of the artery is occluded, Angina

Pectoris will occur

References

• 1. Lippincott’s illustrated reviews: Biochemistry. Richard

A. Harvey, Denise R. Ferrier. 5thed, 2011. Introduction to

Carbohydrates. Ch. 7, p: 83-90.Lippincott Williams &

Wilkins.

• 2. Harpers illustrated Biochemistry. Robert K. Murray,

Daryl K. Granner, Peter A. Mayes, Victor W. Rodwell.

26th ed, 2003. Carbohydrates of Physiologic

Significance. Peter A. Mayes, David A. Bender. Ch. 13,

p: 102-10. Lange Medical Books/Mc Graw-Hill.

Many Thanks