Sterol regulation of HMG CoA reductase in the liver

HMG CoA reductase is the molecular target of statins, which are widely used to treat hypercholesterolemia and associated atherosclerosis in humans. HMG CoA reductase catalyzes the conversion of HMG CoA to mevalonate, a rate‐limiting step in the synthesis of cholesterol and nonsterol isoprenoids. Mevalonate‐derived sterol and nonsterol isoprenoids exert tight feedback regulation on reductase by inhibiting transcription of the reductase gene, blocking translation of reductase mRNAs, and accelerating degradation of reductase protein. In this study, the sterol‐accelerated degradation of the membrane domain of HMG CoA reductase, a component of the reductase that is both necessary and sufficient for sterol‐accelerated degradation, was examined in the liver of transgenic mice overexpressing reductase. The contribution of the reaction to the overall regulation of the reductase in the organ was also determined. By focusing directly on sterol‐accelerated degradation, these studies allowed determination of protein stability in the overall regulation of reductase in the liver to be accessed. Elucidation of the molecular mechanisms controlling reductase degradation in vivo will allow for the development of novel therapies that increase the effectiveness of statins in lowering blood cholesterol. Funding from Howard Hughes Medical Institute supported this research.