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Differential Expression of the Host Lipid Regulators ANGPTL-3 and ANGPTL-4 in HCV Infection and Treatment
Authors:Vaia Valiakou  Petros Eliadis  Eirini Karamichali  Ourania Tsitsilonis  John Koskinas  Urania Georgopoulou  Pelagia Foka
Affiliation:1.Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (V.V.); (E.K.);2.Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece;3.Department of Biology, National and Kapodistrian University of Athens (NKUA), 15784 Athens, Greece;4.2nd Department of Internal Medicine, Medical School of Athens, Hippokration Hospital, 11521 Athens, Greece;
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.
Keywords:angiopoietin-like proteins, HCV infection, fingerprint, lipid metabolism, DAA, liver, cirrhosis, fibrosis, TGF-β  , hepatocellular carcinoma
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