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on the hepatocyte surface and which is the main mechanism for the removal of

LDL from plasma. This observation stimulated the research for drugs that would

increase LDL receptor expression and a reduction in plasma LDL. However, to date

the main attention for the therapeutic reduction of plasma cholesterol has focussed

on the metabolic pathway, starting with acetyl CoA, which leads to its biosynthesis.

The controlling enzyme in this pathway is hydroxymethylglutaryl CoA reductase

(HMG CoA reductase):

Dietary
fat
Intestine
ABCA1

Blood

Chylomicrons

Muscle

Liver

LDLR

ABCA1

SR-BI

Chylomicron

remnants

Fatty acids Fatty acids

Adipose

tissue

Nascent

HDL

apoA–I

Cholesteryl

ester

Mature HDL

apoB

PLTP CETP

LCAT

Nascent

HDL

Triglyceride

Cholesteryl ester

VLDL and LDL

Peripheral tissues

Free cholesterol

ABCG1

Nucleus

ABCA1 Macrophage

LXR

Fig. 18.4Lipoprotein metabolism. The intestine absorbs dietary fat and packages it into chylomicrons that are

transported to peripheral tissues through the blood. In muscle and adipose tissues the enzyme lipoprotein

lipase breaks down the chylomicrons, and fatty acids enter these tissues. The liver takes up the chylomicron

remnants, loads lipids onto apoB and secretes VLDL that undergoes lipolysis by lipoprotein lipase to form

LDL. LDLs are taken up by LDL receptors (LDLR) on liver cells. The intestine and liver generate HDL particles

through the secretion of lipid-free apoA1. This recruits cholesterol through the action of the transporter ABCA1

forming nascent HDLs. The free cholesterol in nascent HDLs is esterified by the enzyme lecithin cholesterol

acyltransferase (LCAT) creating mature HDLs. The cholesterol in mature HDLs is returned to the liver

directly through the receptor SR-B1 and indirectly by transfer to LDLs and VLDLs through the enzyme cholesteryl

ester transfer protein (CETP). The lipid content of HDLs is also altered by the enzymes hepatic lipase and

endothelial lipase and the phospholipids transfer protein (PLTP). (Adapted from Rader, D. J. and Daugherty,

A. (2008). Translating molecular discoveries into new therapies for atherosclerosis.Nature, 451 , 904–912, by

permission of the Nature Publishing Group.)

Acetyl CoA HMG CoA

2NADPH + 2H+2NADP

CoA

Feedback inhibition (–)

HMG CoA reductase

Mevalonic acid Cholesterol

Statins

®® ®®®®®

721 18.2 Drug discovery