Human Biochemistry Volume 1 - Murray R. 1993

Bioenergetics and Carbohydrate and Lipid Metabolism
Synthesis, Transport, and Excretion of Cholesterol
Biosynthesis of Cholesterol - Regulation of Cholesterol Synthesis

The regulation of Cholesterol synthesis occurs at an early stage of the pathway. In starved rats, a marked decrease in HMG-CoA reductase activity is observed, which accounts for the reduced cholesterol synthesis during fasting. HMG-CoA reductase is inhibited in the Liver by cholesterol via a feedback mechanism. Since direct Enzyme Inhibition is not observed, cholesterol (or a metabolite thereof, such as an oxidized sterol) likely acts indirectly: either by suppressing the de novo Synthesis of the reductase or by inducing the synthesis of Enzymes that catalyze reductase inactivation. Cholesterol synthesis is also inhibited by cholesterol-containing LDL upon binding to their respective receptors (apo-B-100 receptors). The rate of cholesterol synthesis and HMG-CoA reductase activity fluctuate depending on the time of day. The results of several studies indicate a remarkably rapid effect of cholesterol on reductase activity, which cannot be explained solely by an influence on the enzyme's synthesis rate. Upon administration of Insulin or thyroid hormone, HMG-CoA reductase activity increases, whereas administration of Glucagon or glucocorticoids decreases it. HMG-CoA reductase can exist in either an active or inactive state. The transition between these states occurs via phosphorylation and dephosphorylation reactions, some of which appear to be cAMP-dependent and are therefore regulated by glucagon (Fig. 27.4). The Effect of dietary cholesterol intake on endogenous cholesterol production was studied in rats. When the diet contained only 0.05% cholesterol, 70–80% of the cholesterol detected in the liver, Small Intestine, and Adrenal Glands was synthesized endogenously, whereas when the diet contained 2% cholesterol, endogenous cholesterol synthesis decreased. However, even with an increased dietary cholesterol content, a complete cessation of Cholesterol synthesis in the body does not occur. Apparently, only hepatic cholesterol production is inhibited. Experiments with the perfused liver demonstrated that cholesterol-rich chylomicron remnants (see p. 264) inhibit cholesterol synthesis.

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Fig. 27.4. Proposed Mechanisms for the regulation of cholesterol synthesis by HMG-CoA reductase.

Fi^g. 27.5. Factors influencing cellular cholesterol Homeostasis. C — cholesterol; CE — cholesteryl esters; ACAT — acyl-CoA:cholesterol acyltransferase; LCAT — lecithin-cholesterol acyltransferase; A-I — apolipoprotein A-I; LDL — low-density Lipoproteins; VLDL — very low-density lipoproteins.

The extent of inhibition of Cholesterol Biosynthesis by dietary cholesterol varies among individuals. Nevertheless, reducing dietary cholesterol intake can help lower Blood cholesterol levels.