A Novel Control Point in Cholesterol Biosynthesis

Abstract

Targeting the cholesterol synthesis pathway has proved invaluable for the treatment of heart disease, as exemplified by the success of the statins. This class of drugs targets 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR), which is billed as the ‘rate‐limiting’ enzyme. Perhaps due to the success of the statins, relatively little is known about the other enzymes involved in cholesterol synthesis, including squalene monooxygenase (SM). SM carries out the first oxygenation step on squalene, before cyclization into the basic steroid structure. Our aim was to investigate the regulation of SM using Chinese hamster ovary (CHO) cells as a model cell system. Surprisingly, cholesterol treatment caused the accumulation of squalene, suggesting that SM may serve as a ‘rate‐limiting’ enzyme beyond HMGCR. This squalene accumulation was also seen in mutant CHO cells that have sterol‐independent transcription, implying that cholesterol regulates SM post‐transcriptionally. Indeed, we found that SM protein was degraded within hours of cholesterol treatment. Proteasomal inhibition blocked SM degradation and reversed the squalene accumulation observed with cholesterol treatment, indicating that the cholesterol‐induced degradation of SM is a flux controlling step in cholesterol synthesis. Therefore, we have identified a significant new control point in the feedback regulation of cholesterol synthesis.