Cholesterol: Sources, Absorption, Function, and Metabolism
Regulation of cholesterol synthesis can be explained in simple economic terms. As with every efficient economy, the supply of cholesterol is geared toward the cellular demand for the molecule. Making cholesterol de novo is energetically expensive, hence the cheapest option for the cell is to derive premade cholesterol by taking up circulating lipoproteins. Cholesterol synthesis is therefore aimed at supplementing that exogenous supply based on demand; production is decreased when supply of exogenous cholesterol is adequate and ramped up in response to increased cholesterol demand. Because too much cholesterol is harmful to the cell, elaborate mechanisms have evolved to tightly regulate its levels by a negative feedback control mechanism. Indeed, cholesterol synthesis was one of the first examples of feedback control of a biosynthetic pathway. More than 80 years ago, Rudolph Schoenheimer9 found that feeding mice cholesterol reduced its synthesis (Schoenheimer and Breusch, 1933). The following section outlines the major modes for regulation of cholesterol synthesis. Much of this work has focused on the rate-limiting step catalyzed by HMGCR, but it is important to note that other enzymes play critical roles, and will be areas of future investigation. Furthermore, different levels of regulation take effect over time (see Figure 13 for an example with HMGCR). The slowest regulation occurs through transcriptional downregulation, where the active enzyme remains but will not be replenished. Next is posttranslational degradation, which marks enzymes for destruction, and then posttranslational modification which is the fastest mode of regulation, as the modification can immediately affect enzyme activity.
D.J. McNamara, in Encyclopedia of Human Nutrition (Third Edition), 2013