Abstract 420: Proprotein Convertase Subtilisin/Kexin 6 Is Involved In Lipid Metabolism In Liver

Abstract

Introduction: PCSK6 is a protease that activates cytokines and growth factors and strongly enriched in healthy human liver, however its function in this context has not been explored. We have previously shown that PCSK6 is induced in atherosclerotic plaques from patients with symptoms of stroke and important for regulating several cell types in this context. Here, we aimed to investigate the role of PCSK6 in lipid metabolism in liver, particularly in the context of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Methods: We used publically available datasets and several atherosclerosis biobanks to investigate the expression of PCSK6 in healthy and diseased human tissues. In addition, we used full Pcsk6 -/- mice as well as liver specific conditional Pcsk6 -/- knockout mice compared to littermate controls, to investigate the effects of PCSK6 ablation on lipid metabolism. Results: Genetic analyses of the PCSK6 locus identified a variant, rs7181043, that was significantly associated with PCSK6 mRNA expression in healthy human adipose tissue, liver and in atherosclerotic plaques. The same variant was associated specifically with plaque fat content and atherosclerotic patient’s plasma LDL levels. In addition, PCSK6 mRNA expression in plaques was positively correlated with total plasma cholesterol and LDL levels in atherosclerotic patients as well as lipid metabolism associated pathways within the carotid plaque. Microarray comparison of the livers from Pcsk6 -/- mice and controls showed that VLDL particle assembly was one of the upregulated processes. I n vivo studies showed that Pcsk6 -/- mice have higher plasma cholesterol and LPL levels at baseline compared to controls, and lower levels of LDLR in their liver. These findings were further confirmed in liver specific conditional knockouts. Preliminary results show that liver specific knockout mice develop increased liver steatosis and fibrosis on a modified western diet. Conclusions: Our data suggests that PCSK6 is involved in cholesterol and metabolic control in liver. Breeding of liver specific Pcsk6 knockout mice on an ApoE -/- background is currently ongoing and will provide insight into the role of liver PCSK6 in atherosclerosis and NAFLD development.