Metabolic impact of extrahepatic PCSK9 modulation: Extrahepatic PCSK9 modulation

Abstract

The Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) protease is a 692 amino acid glycoprotein which belongs to the proprotein convertase family. PCSK9 binds several receptors of the LDL family, including VLDLR, LRP1 but also with CD36, driving their lysosomal degradation. From the beginning of the 21st century a growing body of interest raised around the opportunity to pharmacologically inhibit PCSK9, and most recently, monoclonal antibodies have been successfully tested for the treatment of severe/genetic forms of dyslipidemia. Despite the majority of circulating PCSK9 being produced by the liver, other organs come into play contributing to its production, such as the heart, the pancreas, and the brain. Nonetheless, extrahepatic PCSK9 may exert a local/paracrine and or autocrine metabolic impact in the homeostatic regulation of cholesterol metabolism, suggesting that, opposite to the liver, in other tissue PCSK9 deficiency or inhibition could contribute to the development of specific organ and tissues dysfunctionalities.