PCSK9: a view beyond the canonical cholesterol lowering impact.

Abstract Proprotein convertase subtilisin kexin/type 9 (PCSK9), mainly synthetized and released by the liver, represents one of the key-regulators of low-density lipoprotein cholesterol (LDL-C). Although genetic and pharmacological studies have undoubtedly demonstrated that lowering PCSK9 levels corresponds to a cardiovascular (CV) benefit, identification of non-cholesterol-related processes have clearly emerged since its discovery. Besides liver, PCSK9 is also expressed in many tissues, e.g., intestine, endocrine pancreas and brain. Thus, aim of the present review is to describe and discuss PCSK9 pathophysiology and possible non-lipid lowering effects whether already extensively characterized (e.g., inflammatory burden of atherosclerosis, triglyceride-rich lipoprotein metabolism, platelet activation), or to be unraveled (e.g., in adipose tissue). The identification of novel transcriptional factors in the promoter region of human PCSK9 (e.g., ChREBP) characterizes new mechanisms explaining how controlling intrahepatic glucose may be a therapeutic strategy to reduce CV risk in type 2 diabetes. Finally, the evidence describing PCSK9 as involved in cell proliferation and apoptosis raises the question of whether or not this protein is involved in cancer risk.