Differential expression of the host lipid regulators angptl‐3 and angptl‐4 in hcv infection and treatment

Abstract

Host lipid metabolism reprogramming is essential for hepatitis C virus (HCV) infection and progression to severe liver disease. Direct‐acting antivirals (DAAs) achieve a sustained virological response (SVR) in most patients, but virus eradication does not always protect against hepatocellular carcinoma (HCC). Angiopoietin‐like protein‐3 (ANGPTL‐3) and angiopoietin‐like protein‐ 4 (ANGPTL‐4) regulate the clearance of plasma lipids by inhibiting cellular lipase activity and possess emerging roles in tumourigenesis. We used ELISA and RT‐qPCR to investigate ANGPTL‐3 and ANGPTL‐4 expression in HCV patients with characterised fibrosis throughout the natural history of hepatitis C and in long‐term HCV infection in vitro, before and after DAA treatment. ANGPTL‐ 3 was decreased in patients with advanced fibrosis compared to other disease stages, while ANGPTL‐4 was progressively increased from acute infection to cirrhosis and HCC, peaking at the advanced fibrosis stage. Only ANGPTL‐3 mRNA was down‐regulated during early infection in vitro, although both ANGPTLs were increased later. DAA treatment did not alter ANGPTL‐3 levels in advanced fibrosis/cirrhosis and in HCV infection in vitro, in contrast to ANGPTL‐4. The association between ANGPTLs and fibrosis in HCV infection was underlined by an inverse correlation between the levels of ANGPTLs and serum transforming growth factor‐ β (TGF‐β). Collectively, we demonstrate the pivotal role of advanced fibrosis in defining the expression fate of ANGPTLs in HCV infection and after treatment and propose a role for ANGPTL‐3 as a contributor to post‐treatment deregulation of lipid metabolism that could predispose certain individuals to HCC development.