A Textbook of Clinical Pharmacology and Therapeutics

in bile into the intestine, where they are involved in fat absorp-
tion. The rate-limiting enzyme in cholesterol biosynthesis is 3-
hydroxyl 3-methylglutaryl coenzyme A reductase (HMG CoA
reductase). Fat is absorbed in the form of triglyceride-rich chy-
lomicra. Free fatty acid is cleaved from triglyceride in these par-
ticles by lipoprotein lipase, an enzyme on the surface of
endothelial cells. Free fatty acids are used as an energy source by
striated muscle or stored as fat in adipose tissue. Chylomicron
remnants are taken up by hepatocytes to complete the exoge-
nous cycle. The endogenous cycle consists of the secretion of
triglyceride-rich (and hence very-low-density) lipoprotein parti-
cles (VLDL) by the liver into the blood, followed by removal
of free fatty acid by lipoprotein lipase. This results in progressive
enrichment of the particles with cholesterol, with an increase
in their density through intermediate-density to low-density

lipoprotein (LDL). Low-density-lipoprotein particles bind to

receptors (LDL receptors) located in coated pits on the surface

of hepatocytes, so the plasma concentration of LDL is deter-

mined by a balance between LDL synthesis and hepatic

uptake. Low-density lipoprotein that enters arterial walls

at sites of endothelial damage can be remobilized in the form

of high-density lipoprotein (HDL), or may become oxidized

and be taken up by macrophages as part of atherogenesis

(see below).

Transgenic mice deficient in specific key enzymes and

receptors in lipoprotein metabolism are useful models, but

most of our understanding of atheroma comes from human

pathology and from experimental studies in primates. Intimal

injury initiates atherogenesis, which is a chronic inflammatory

process. Rheological factors (e.g. turbulence) are believed to be

178 PREVENTION OF ATHEROMA:LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES

4.8 6.0 7.2 8.4 4.8 6.0

Low risk

Non-cigarette smoker

Glucose intolerance absent

No ECG-LVH

ECG-LVH present

High risk

Cigarette smoker

Glucose intolerance

present

195

165

135

105

7.2 8.4

Serum cholesterol level (mmo/L)

195 mmHg

165 mmHg

135 mmHg

105 mmHg

35

30

25

20

15

10

Probability of developing CHD (%) 5

Average risk

Figure 27.2:Probability of developing coronary heart

disease in six years: 40-year-old men in the Framingham

Study during 16 years follow up. The numbers to the

right of the curves show the systolic blood pressure

(mmHg).

Lipoprotein pathways

Exogenous Endogenous

Dietary fat

Bile acid

Cholesterol

Fat

Muscle

Fat

Muscle

FFA FFA

Lipoprotein

lipase

Lipoprotein

lipase

Liver

Chylomicron Remnant VLDL IDL HDL

LDL Tissue

Intestine



Figure 27.3:Lipoprotein transport. FFA, free fatty acids; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein;
HDL, high-density lipoprotein.