☆ 4.6 Article

Hepatitis C virus core protein stimulates fibrogenesis in hepatic stellate cells involving the obese receptor

JOURNAL OF CELLULAR BIOCHEMISTRY (2013)

期刊

JOURNAL OF CELLULAR BIOCHEMISTRY

卷 114, 期 3, 页码 541-550

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WILEY-BLACKWELL

DOI: 10.1002/jcb.24392

关键词

HEPATITIS C VIRUS CORE PROTEIN; OXIDATIVE STRESS; HEPATIC STELLATE CELL; OBESE RECEPTOR B (OB-RB); AMP-ACTIVATED PROTEIN KINASE (AMPK); JANUS KINASE 2 (JAK2); SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)

类别

Biochemistry & Molecular Biology Cell Biology

资金

National Science Council [NSC 100-2325-B-010-002, NSC 99-2628-B-010-002-MY3, NSC 96-2628-B-077-001-MY2, NSC 97-2628-B-077-001, NSC 99-2628-B-077-001-MY3]
National Research Institute of Chinese Medicine [NRICM100-DBCM-05]

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摘要

Hepatitis C virus core protein (HCVcp), which is secreted by infected cells, is reported as an immunomodulator in immune cells. However, the effects of HCVcp on hepatic stellate cells (HSCs), the key cells in liver fibrosis, still remain unclear. In this study, we investigated the effects of HCVcp on obese receptor (ObR) related downstream signaling pathways and fibrogenic gene expression in HSCs. LX-2, a human HSC line, was incubated with HCVcp. Inhibitors and short interfering RNAs were used to interrogate the mechanisms of HCVcp action on HSCs. HCVcp (20-100?ng/ml) concentration-dependently stimulated a-smooth muscle actin (a-SMA) protein expression and mRNA expression of a-SMA, procollagen a2(I) and TGF-beta 1 genes, with a plateau of 220% of controls at 100?ng/ml. HCVcp induced mRNA and protein expression of ObR. Blocking of Ob-Rb with a neutralizing antibody inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and AMPKa stimulated by HCVcp. Furthermore, knockdown of Ob-Rb down-regulated HCVcp-induced STAT3, AKT, and AMPKa phosphorylation, and reversed HCVcp-suppressed mRNA expression of matrix metalloproteinase (MMP)-1, peroxisome proliferator-activated receptor (PPAR)? and sterol regulatory element binding protein-1c (SREBP-1c) genes. AMPKa signaling blockade reversed HCVcp-suppressed SREBP-1c mRNA expression. HCVcp stimulated reactive oxygen species formation and gp91phox (a component of NADPH oxidase) protein expression, together with AKT phosphorylation, leading to suppression of PPAR? and SREBP-1c genes. Our results provide a new finding that HCVcp induced ObR-dependent Janus Kinase (JAK) 2STAT3, AMPKa, and AKT signaling pathways and modulated downstream fibrogenetic gene expression in HSCs. J. Cell. Biochem. 114: 541550, 2013. (C) 2012 Wiley Periodicals, Inc.

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