PCSK9: a new target for lipid lowering treatment

Familial hypercholesterolemia is characterized by high concentrations of cholesterol associated with Low density lipoprotien (LDL-C). Until now, it was thought that the dominat autosomic form of the disease was caused by mutations of the LDL receptor (LDLr) or of its ligand the apolipoprotein B. Recently a third gene was identified: proprotein convertase subtilisin/kexin type 9 (PCSK9 or Narc-1). Deficiency of PCSK9 is associated with very low levels of LDL-C and a very significant reduction of cardiovascular disease. In vitro studies and investigations in mice show that PCSK9 is a natural inhibitor of the LDLr and that the gene's regulation is more complicated than initially thought. In addition to its effect on LDL catabolism, the debate over its role on apoB/VLDL production and hypertriglyceridemia is very much alive. Developing inhibitors of PCSK9 -or transcriptional repressors ?- should help amplify the beneficial effect of statins and therefore improve the patient's lipid levels. For these reasons, PCSK9 has become a very promising therapeutic target.