The small heterodimer partner inhibits activation of hepatic stellate cells via autophagy.

Abstract

Hepatic fibrosis is a health concern worldwide, and it is of great importance to develop effective therapeutic targets. The small heterodimer partner (SHP) is a regulator of lipid and bile acid metabolism in the liver. The objective of this study was to investigate the contribution of SHP to hepatic fibrosis and the underlying mechanism. An in vivo rat model of hepatic fibrosis was created through treatment with carbon tetrachloride. We used arginine-glycine-aspartic acid-poly (ethylene glycol)-polyethyleneimine (RGD-PEG-PEI) for the specific transfer of SHP into hepatic stellate cells (HSC). The level of gene expression was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The LX2 cell line was selected for the in vitro assay. Artificial activation of LX2 in vitro was conducted through treatment with platelet-derived growth factor-BB (PDGF-BB), and autophagy was activated using rapamycin. Gain and loss of function assays were performed using a SHP-expressing plasmid or siRNA-SHP. Both qRT-PCR and western blotting were utilized to detect the level of gene expression. RGD-PEG-PEI-mediated the specific transduction of SHP into HSC in the liver and effectively increased the expression of SHP in the rat liver. After treatment with RGD-PEG-PEI-SHP, downregulation of liver fibrosis-associated genes was observed. The results of the in vitro assay indicated that SHP attenuated the stimulating effect of PDGF-BB on the activation of LX2 cells. Overexpression of SHP leads to significant downregulation of HSC activation-associated molecular factors, including α-smooth muscle actin, tissue inhibitor of metalloproteinase-1, and type I collagen. Conversely, increased expression of these molecules could be observed following knockdown of SHP. Furthermore, SHP affected fibrosis by inhibiting autophagy activated through treatment with rapamycin in LX2 cells. Overexpression of SHP may prevent liver fibrogenesis through inhibition of autophagy in HSC. The SHP may prevent liver fibrogenesis through inhibition of autophagy in HSC. A SHP-targeting therapy-based anti-fibrosis strategy possesses potential for application to the treatment of liver fibrosis.