Navigating the Shallows and Rapids of Cholesterol Synthesis Downstream of HMGCR.

Cholesterol is vital for human life, but its levels must be tightly regulated. Too little cholesterol leads to developmental disorders, but too much is widely appreciated as contributing to heart disease. Levels are regulated through the coordinated control of cholesterol synthesis, uptake and efflux. Here, we focus on cholesterol synthesis. The cholesterol synthesis pathway involves more than twenty enzymes, but most research so far has focused on a very early enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a well characterised control point. This is largely because HMGCR is the target of the successful cholesterol-lowering drugs, the statins. Our recent work has examined several other enzymes in the pathway and revealed complex regulatory mechanisms that also contribute to the control of cholesterol synthesis. In this review, we discuss the transcriptional regulation of the two terminal enzymes, 7- and 24-dehydrocholesterol reductase (DHCR7 and DHCR24), where we have found that a cooperative transcriptional program exists. We also discuss the post-translational regulation of another critical enzyme, squalene monooxygenase (SM), which has its protein levels controlled by cholesterol, and DHCR24, which has its activity affected by sterols and related compounds, as well as via phosphorylation/signalling. There is an unforeseen complexity in the regulation of cholesterol synthesis which requires further investigation.