Regulation of three key enzymes in cholesterol metabolism by phosphorylation/dephosphorylation.

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Abstract
The role of phosphorylation/dephosphorylation in the regulation of 3 key enzymes in cholesterol metabolism was investigated. 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34), the major regulatory enzyme in cholesterol biosynthesis, is inhibited by phosphorylation. Acyl-CoA:cholesterol O-acyltransferase (ACATase; EC 2.3.1.26) and cholesterol 7.alpha.-hydroxylase (EC 1.14.13.17), key regulatory enzymes in the utilization of cholesterol, are activated by phosphorylation. Short-term regulation of the concentration of intracellular unesterified cholesterol may be achieved by a coordinate phosphorylation/dephosphorylation of these 3 enzymes. For example, if cholesterol enters the liver cell, HMG-CoA reductase would be inhibited by phosphorylation and biosynthesis of cholesterol would be reduced; however, reactions utilizing cholesterol would be activated, due to the phosphorylation of ACATase and cholesterol 7.alpha.-hydroxylase. Thus, the phosphorylation/dephosphorylation of these 3 enzymes provides an elegant short-term mechanism for the homeostasis of intracellular unesterified cholesterol.

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