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Hepatitis C virus core protein stimulates fibrogenesis in hepatic stellate cells involving the obese receptor.
- Source :
-
Journal of cellular biochemistry [J Cell Biochem] 2013 Mar; Vol. 114 (3), pp. 541-50. - Publication Year :
- 2013
-
Abstract
- 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 α-smooth muscle actin (α-SMA) protein expression and mRNA expression of α-SMA, procollagen α2(I) and TGF-β1 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 AMPKα stimulated by HCVcp. Furthermore, knockdown of Ob-Rb down-regulated HCVcp-induced STAT3, AKT, and AMPKα phosphorylation, and reversed HCVcp-suppressed mRNA expression of matrix metalloproteinase (MMP)-1, peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element binding protein-1c (SREBP-1c) genes. AMPKα signaling blockade reversed HCVcp-suppressed SREBP-1c mRNA expression. HCVcp stimulated reactive oxygen species formation and gp91(phox) (a component of NADPH oxidase) protein expression, together with AKT phosphorylation, leading to suppression of PPARγ and SREBP-1c genes. Our results provide a new finding that HCVcp induced ObR-dependent Janus Kinase (JAK) 2-STAT3, AMPKα, and AKT signaling pathways and modulated downstream fibrogenetic gene expression in HSCs.<br /> (Copyright © 2012 Wiley Periodicals, Inc.)
- Subjects :
- AMP-Activated Protein Kinases antagonists & inhibitors
AMP-Activated Protein Kinases metabolism
Actins biosynthesis
Actins genetics
Antibodies, Neutralizing immunology
Cell Line
Collagen Type I genetics
Hepacivirus genetics
Hepacivirus metabolism
Hepatic Stellate Cells virology
Hepatitis C Antigens genetics
Humans
Janus Kinase 2 metabolism
Matrix Metalloproteinase 1 genetics
PPAR gamma genetics
PPAR gamma metabolism
Proto-Oncogene Proteins c-akt metabolism
RNA Interference
RNA, Messenger biosynthesis
RNA, Small Interfering
Reactive Oxygen Species metabolism
Receptors, Leptin genetics
Receptors, Leptin immunology
STAT3 Transcription Factor antagonists & inhibitors
STAT3 Transcription Factor metabolism
Sterol Regulatory Element Binding Protein 1 genetics
Transforming Growth Factor beta1 genetics
Viral Core Proteins genetics
Hepatic Stellate Cells metabolism
Hepatitis C Antigens metabolism
Liver Cirrhosis
Receptors, Leptin metabolism
Viral Core Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4644
- Volume :
- 114
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cellular biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22961938
- Full Text :
- https://doi.org/10.1002/jcb.24392