Regulation of three key enzymes in cholesterol metabolism by phosphorylation/dephosphorylation.
Our laboratories have investigated the role of phosphorylation/dephosphorylation in the regulation of three key enzymes in cholesterol metabolism. 3-Hydroxy-3-methylglutarylcoenzyme A (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 1.14.13.7), key regulatory enzymes in the utilization of cholesterol, are activated by phosphorylation. In view of these results, we propose that short-term regulation of the concentration of intracellular unesterified cholesterol is achieved by a coordinate phosphorylation/dephosphorylation of these three 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 three enzymes provides an elegant short-term mechanism for the homeostasis of intracellular unesterified cholesterol.
D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D006706:Homeostasis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D013250:Steroid Hydroxylases / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000378:metabolism*
D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D000217:Acyltransferases; D002785:Sterol O-Acyltransferase