Small heterodimer partner attenuates profibrogenic features of hepatitis C virus-infected cells.

BACKGROUND & AIMS: An atypical orphan nuclear receptor small heterodimer partner (SHP) is known to be regulated by AMP-activated protein kinase (AMPK). Both of them inhibit TGF-β and Smad signalling and exhibit antifibrotic activity in the liver. However, little is known about the protective effects of SHP and AMPK against hepatitis c virus (HCV)-induced hepatic fibrosis.

METHODS: Levels of SHP, p-AMPK and fibrotic markers in HCV-infected human liver and in Huh-7.5 cells infected with HCV genotype 2a (JFH-1) were investigated. The effect of adenovirus-mediated overexpression of SHP (Ad-SHP) and AMPK activation via metformin and 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) on fibrotic gene expression was evaluated in HCV-infected cells. Finally, we examined the effect of Ad-SHP and AMPK activators on invasion and activation of LX2 human HSCs induced by conditioned media from HCV-infected hepatocyte (CM).

RESULTS: In HCV-infected human livers and Huh-7.5 cells infected with HCV, SHP mRNA and protein levels were diminished compared with controls, whereas profibrotic factors were increased. Pharmacological AMPK activation recovered SHP expression, and Ad-SHP inhibited HCV-induced fibrotic gene expression. This finding was accompanied by inhibition of HCV-stimulated nuclear factor-kappa B, an inducer of TGF-β. Moreover, CytoSelect invasion assay revealed that enhanced activity and invasiveness of hepatic stellate cells induced by CM.

CONCLUSION: These results demonstrate that overexpression of SHP and activation of AMPK reverses profibrogenic features of HCV-infected cells by decreasing TGF-β and fibrotic gene expression. These findings provide a rationale for SHP as a possible therapeutic target against HCV-induced hepatic fibrosis.