Cholesterol Synthesis Is Controlled By Regulation Of HmgcoA Reductase

Regulation of cholesterol synthesis is exerted near the beginning of the pathway, at the HMG-CoA reductase step. The reduced synthesis of cholesterol in starving animals is accompanied by a decrease in the activity of the enzyme. However, it is only hepatic synthesis that is inhibited by dietary cholesterol. HMG-CoA reductase in liver is inhibited by mevalonate, the immediate product of the pathway, and by cholesterol, the main product. Cholesterol (or a metabolite, eg, oxygenated sterol) represses transcription of the HMG-CoA reductase gene and is also believed to influence translation. A diurnal variation occurs in both cholesterol synthesis and reductase activity. In addition to these mechanisms regulating the rate of protein synthesis, the enzyme activity is also modulated more rapidly by posttransla-tional modification (Figure 26-4). Insulin or thyroid hormone increases HMG-CoA reductase activity, whereas glucagon or glucocorticoids decrease it. Activity is reversibly modified by phosphorylation-dephos-phorylation mechanisms, some of which may be cAMP-dependent and therefore immediately responsive to glucagon. Attempts to lower plasma cholesterol in humans by reducing the amount of cholesterol in the diet produce variable results. Generally, a decrease of 100 mg in dietary cholesterol causes a decrease of approximately 0.13 mmol/L of serum.

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