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.
Highlights
Hepatitis C is a viral disease with a global geographical distribution, with approximately 71,000,000 people chronically infected worldwide [1]
Genotyping analysis revealed that hepatitis C virus (HCV) genotypes-1a, -1b, -2a, -3 and -4 were encountered in our samples at varied levels, except for a small percentage of samples for which there was no available record of the viral load (VRL) or genotype
Depending on their clinical presentation and the METAVIR fibrosis score (Fn) recorded at the onset of therapy, the patients were categorised into the following disease stage groups: acute infection (F0/F1), mild fibrosis (F0/F1/F2), advanced fibrosis (F3), cirrhosis (F4) and HCV-induced hepatocellular carcinoma (HCC) (F4)
Summary
Hepatitis C is a viral disease with a global geographical distribution, with approximately 71,000,000 people chronically infected worldwide [1]. Chronicity is established in 60–80% of hepatitis C virus (HCV)-infected individuals, accompanied by an increased risk for cirrhosis development within the 20 years. HCV viral proteins, mainly core and non-structural 5A (NS5A), orchestrate de novo lipogenesis and enhance hepatic lipid uptake and attenuation of fatty acid catabolism through modulation of lipid-related transcription factors, thereby promoting hepatic steatosis [4,5]. Development of hepatic fibrosis, a hallmark of HCV infection, occurs roughly at the same time. It is characterised by the excessive production of extracellular matrix (ECM) proteins from activated hepatic stellate cells (HSCs) [6]. The molecular mechanisms that link steatosis with hepatic fibrosis are poorly defined in HCV infection. Continuous disturbance of the beneficial wound-healing processes that are part of the standard response-to-injury regeneration programme leads from set-in fibrosis to cirrhosis [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
