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ASPP2 Inhibits the Profibrotic Effects of Transforming Growth Factor-?1 in Hepatic Stellate Cells by Reducing Autophagy.

ABSTRACT: Apoptosis-stimulating protein of p53-2 (ASPP2) is a damage-inducible P53-binding protein that enhances damage-induced apoptosis. Fibrosis is a wound-healing response, and hepatic stellate cells (HSCs) are key players in liver fibrogenesis. However, little is known about the relationship between ASPP2 and hepatic fibrosis.We investigated the effects of ASPP2 overexpression in HSCs and the role of ASPP2 in mouse liver fibrogenesis.Human HSCs (LX-2 cells) were pre-incubated with GFP adenovirus (Ad) or ASPP2 adenovirus (AdASPP2) for 24 h and then treated with or without TGF-?1. ASPP2+/- and ASPP2+/+ Balb/c mice were used to examine the effects of ASPP2 on liver fibrosis in vivo. ASPP2+/+ Balb/c mice were generated by injecting AdASPP2 into the tail vein of ASPP2 WT Balb/c mice; all mice received intraperitoneal injections of carbon tetrachloride.In this study, ASPP2 was found to markedly inhibit TGF-?1-induced fibrogenic activation of LX-2 cells. Further experiments using an autophagic flux assay confirmed that ASPP2 reduced the fibrogenic activation of LX-2 cells by inhibiting autophagy. Moreover, we found that ASPP2 overexpression attenuated the anti-apoptotic effects of TGF-?1 in LX-2 cells. The extent of liver fibrosis was markedly reduced in ASPP2+/+ mouse liver tissue compared with control mice; however, in ASPP2+/- mice, hepatic collagen deposition was significantly increased.These results suggest that TGF-?1-induced autophagy is required for the fibrogenic response in LX-2 cells and that ASPP2 may both inhibit TGF-?1-induced autophagy and decrease liver fibrosis.


PROVIDER: S-EPMC5760593 | BioStudies | 2018-01-01T00:00:00Z

REPOSITORIES: biostudies

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