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

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.

miR‐222 Overexpression May Contribute to Liver Fibrosis in Biliary Atresia by Targeting PPP2R2A

“…Phosphoinositide 3-kinase/Akt signaling is one of the more important pathways involved in cellular functions, such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking, and is frequently activated during liver fibrosis (23,24). In this study, we showed that miR-222 inhibition induced a significant reduction in Akt phosphorylation, which supports the notion that miR-222 may be involved in Akt activation.…”

Human hepatic stellate cells are not permissive for hepatitis C virus entry and replication

“…Alternatively, HCV could bind to and activate HSCs without the need to infect them. Previous studies have suggested that HCV viral proteins can activate HSCs after direct interaction with their plasma membrane in various in vitro experiments 7 8 35 36. Such an interaction could happen without the need for HSC infection if the viral particles that express folded HCV envelope glycoproteins at their surface can bind to HSCs and binding activates intracellular pathways, as suggested by Mazzocca et al 8 The physiological role of the core and non-structural proteins is more difficult to envisage in the absence of HSC infection by HCV.…”

The evaluation of fibrotic effects of the hepatitis B virus pre-core in hepatic stellate cells

“…A previous study provided direct evidence that HBV could replicate and express structural proteins in HSCs cells (4). In spite of different reports concerning the profound role of HCV core protein in liver fibrosis, the impact of HBV core protein remains to be elucidated in HSCs (5)(6)(7)(8).…”

“…In spite of some reports concerning fibrotic roles of HCV core protein (5)(6)(7)(8), the impact of the HBV core protein (HBc) on HSCs is described poorly. The HBc is the primary structural unit of the capsid, consisting of 185 amino acids.…”