Pancreatic PCSK9 and its involvement in diabetes

Maaike Kockx, Leonard Kritharides


Hepatic expression of the low-density lipoprotein receptor (LDLR) is one of the main regulators of plasma low-density lipoprotein cholesterol (LDL-C) and has been an important target for the primary and secondary prevention of coronary disease. Increasing cell surface LDLR levels in the liver enhances clearance of LDL particles from the circulation, lowering plasma LDL-C levels. Statins inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme for cholesterol synthesis, thereby lowering intracellular cholesterol levels. This will induce processing of sterol regulatory element-binding protein-2 (SREBP2), leading to increased surface expression of LDLR and lowering of plasma LDL levels (1). Statins have been proven to reduce coronary events in proportion to the degree to which they lower LDL cholesterol, with approximately 20% reduction in events for every 1 mmol lowering of LDL cholesterol (2).