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21 September 2017 : Laboratory Research  

Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis

Hiroko Takaki1ABCDEF, Yuko Akazawa23A*, Youko Kido2B, Mami Morishita1BC, Takuya Honda1D, Hidetaka Shibata1D, Satoshi Miuma1D, Hisamitsu Miyaaki1AD, Naota Taura1D, Hisayoshi Kondo4C, Kazuhiko Nakao1DG

DOI: 10.12659/MSM.903210

Med Sci Monit 2017; 23:4526-4532

Abstract

BACKGROUND: Hepatitis C virus (HCV) infection and metabolic diseases including nonalcoholic steatohepatitis (NASH) exhibit a complex interplay. Although free fatty acid-mediated apoptosis is a prominent feature of NASH, the impact of HCV infection on hepatocyte lipotoxicity has remained largely unexplored. The study aimed at identifying whether infection by HCV affected the apoptotic pathway in hepatocytes during fatty acid assault.

MATERIAL AND METHODS: OR6 cells, which are derived from human hepatocellular carcinoma Huh-7 cells and harbor a full-length HCV RNA genome replication system, were treated with palmitate. Apoptosis was examined by 4’,6-diamidino-2-phenylindole staining. Activation and expression of JNK, Bim, cIAP-1, and Mcl-1 were examined by immunoblotting. mRNA expression of CHOP, a major player in endoplasmic reticulum stress-mediated apoptosis, was assessed by real-time PCR.

RESULTS: Palmitate-induced hepatocyte apoptosis was significantly enhanced in OR6 cells compared to cured cells, in which the HCV genome had been eradicated by treatment with interferon-α. Although basal expression of CHOP mRNA was enhanced in OR6 cells compared to cured cells, it was similarly upregulated in both cell lines following palmitate treatment. Notably, palmitate-induced JNK phosphorylation was accentuated in OR6 cells compared to cured cells. Inhibition of JNK with SP600125 attenuated palmitate-induced apoptosis. Palmitate-mediated upregulation of BH3-only protein Bim, which acts downstream of JNK, was also enhanced in OR6 cells compared to cured cells. In contrast, Mcl-1 and cIAP-1 were equally reduced in OR6 cells and cured cells following palmitate treatment.

CONCLUSIONS: These findings suggest that during lipoapoptosis, HCV infection may enhance hepatocyte toxicity by increasing JNK phosphorylation.

Keywords: Cell Death, Fatty Acids, Nonesterified, Fatty Liver, Hepatitis C, Chronic

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750