*Geek Box: The LDL-Receptor

*Geek Box: The LDL-Receptor

 A major breakthrough in cardiovascular sciences was achieved in 1974, when Joseph Goldstein and Micheal Brown discovered that a genetic defect in the gene for the LDL-receptor was the underlying cause of familial hypercholesterolemia [FH].

The LDL-receptor is expressed in cells throughout the body, and its expression is responsible for taking up cholesterol which has been transported by LDL particles to body tissues, i.e., ‘forward cholesterol transport’. By taking up cholesterol from LDL, the cholesterol content of LDL particles is reduced, and circulating levels of cholesterol are lowered.

When the LDL-receptor is defective, as in conditions like FH, or its expression is suppressed through other factors, LDL cannot clear its cholesterol content and LDL remains in circulation carrying cholesterol, increasing the opportunity to cross into the arteries and deposit cholesterol in the artery wall. The discovery by Goldstein and Brown, which won them the Nobel Prize, also lead to the identification of the HMG-CoA-reductase enzyme as the rate-limiting enzyme in cholesterol synthesis, resulting in the development of statins to target the inhibition of this enzyme. By inhibiting HMGCR, cholesterol synthesis in the liver is reduced and the activity of the LDL-receptor is increased, resulting in greater clearance of LDL-C from the circulation, and lower LDL-C levels.

This is a crucial point: every intervention shown to reduce CVD risk does so by ultimately resulting in increased expression of the LDL-receptor. The common pathway of increased LDL-C clearance from circulation is via upregulation of LDL-receptor activity. The mechanism through which this increased LDL-receptor activity is achieved varies from pathway to pathway, including inhibited intestinal absorption, inhibited cholesterol synthesis in the liver, or directly upregulated LDL-receptors. These respective pathways are influenced by genetic variants: NPC1L1 [intestinal absorption], HMGCR [hepatic cholesterol synthesis], and PCSK9 [LDL-receptor activity]. These pathways are the direct targets of various pharmacological interventions: bile acid sequestrates, e.g., ezetimibe [NPC1L1]; hepatic cholesterol synthesis, e.g., statins [HMGCR], and; increased LDL-receptor activity, e.g., PCSK9-inhibitors [PCSK9].

Oh, and this also happens to be the mechanism through which dietary saturated fat influence LDL-C levels and resulting CVD risk: saturated fats result in suppression of the LDL-receptor, impairing cholesterol clearance from the blood. The net result is the same, independent of the underlying mechanism, when the common pathway is increased LDL-C clearance via the LDL-receptor.