Grant: Project Grant

We discovered a mammalian family of 9 enzymes (PCSK1-PCSK9), of which PCSK7 and PCSK9 are unique for their key roles in the regulation of cholesterol & lipid metabolism, with strong translational potential in cardiovascular diseases, inflammatory, vascular, and proliferative pathologies. (A) Our discovery of PCSK9 (2003) led to the development of robust and specific inhibitors (PCSK9i), now prescribed in clinics worldwide for the effective treatment of patients with high LDL-cholesterol. Compared to conventional "statins", these new lipid lowering medicines cause a 20% reduction in the relative risk of developing major cardiac complications. PCSK9 leads to the destruction of receptors, e.g., LDL-cholesterol receptor (LDLR). We demonstrated that both LDLR and the immune major histocompatibility complex (MHC-I) bind PCSK9 and that the combination of LDLR-PCSK9-MHC-I regulates the cellular functions of PCSK9. (B) The physiological and pathological functions of PCSK7 were unknown until we showed that liver derived PCSK7 modulates the development of fatty liver disease by enhancing the secretion of apolipoprotein B (apoB) critical in lipid secretion. Thus, liver-targeted small DNA-like drugs inhibiting PCSK7's expression (PCSK7i) can reverse the formation of hepatic steatosis induced by a high fat-fructose-cholesterol diet, a condition known as Non-Alcoholic Fatty Liver Disease (NAFLD) affecting 25-30% of Canadians. If not treated early, NAFLD can evolve into hepatocellular carcinoma, a major cancer in our society, with no effective treatment. • We will define in more details the structural modifications of PCSK7 and PCSK9 that affect their functions on apoB, LDLR and MHC-I. We will test whether PCSK7i alone or combined with PCSK9i can prevent cardiometabolic diseases, such as fatty liver in wild type mice and in humanized mice generated by us. Our recent discovery of the role of PCSK7 in the treatment of NAFLD should provide tangible translational applications to human.