Recent progresses on feedback regulation of cholesterol biosynthesis

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Cholesterol is essential for membrane function. High level of cholesterol is a major risk factor for atherosclerosis.Cholesterol is synthesized from acetyl-CoA through a cascade of enzymatic reactions.The biosynthesis of cholesterol is tightly regulated,mainly through two feedback regulatory mechanisms: sterolregulated degradation of HMG-CoA reductase (HMGCR) and maturation of sterol regulatory element-binding protein (SREBP).HMGCR catalyzes the conversion of HMG-CoA to mevalonate that is a rate-limiting step in cholesterol biosynthesis.Sterol promotes the degradation of HMGCR through the ubiquitin-proteasome pathway,and therefore slows down cholesterol biosynthesis.Gp7,an ER membrane-anchored ubiquitin ligase,has been identified as the E3 that ubiquitinates HMGCR.Gp78 also mediates the degradation of Insig-l protein.Insig-l and -2are key negative regulators of sterol-regulated proteolysis of SREBP that controls the expression of lipogenic genes. We generated liver-specific gp78 knockout ( L-gp78-"- ) mice and showed that although the degradation of HMGCR was blunted,SREBP was suppressed due to the elevation of Insig-l/-2,and therefore the lipid biosynthesis was decreased.
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