Peroxisome proliferator-activated receptor γ inhibits hepatic stellate cell activation regulated by miR-942 in chronic hepatitis B liver fibrosis

Aims: Liver fibrosis is a chronic liver disease characterized by hepatic stellate cell (HSC) activation. Peroxisome proliferator-activated receptor gamma (PPAR gamma) play an important role in HSC activation. This study aimed to investigate the role of PPAR gamma in the progression of human hepatic fibrosis and the mechanism by which microRNA-942 regulates HSC activation. Methods: 70 chronic hepatitis B (CHB) patients liver tissues were used to assess PPAR gamma, alpha-SMA and miR-942 levels by immunoblot and real-time PCR. Human primary HSCs or LX2 cells were used to perform multiple molecular experiments based on the transfection of small interfering RNA (siRNA) or co-transfection of microRNA inhibitor. Site-directed mutagenesis and luciferase reporter assays were used to identify miR-942 targets. miR-942 expression and localization in hepatic fibrosis and co-localization between alpha-SMA were determined by fluorescence in situ hybridization (FISH). Key findings: The mRNA expression of PPAR gamma was decreased in activated HSCs and CHB patients with liver fibrosis, which was negatively correlated with F stage and alpha-SMA. miR-942 negatively regulates PPAR gamma expression via targeting the PPAR gamma 3'UTR Inhibiting PPAR gamma promoted TGF beta 1 induced HSC activation, and this effect was blocked after inhibiting the miR-942. Moreover, miR-942 was mainly expressed in fibrous septa and negatively correlated with PPAR gamma in liver fibrosis. Significance: PPAR gamma targeting by miR-942 and decreasing HSC activation in human hepatic fibrosis. Hence, regulating PPAR gamma may be a promising therapeutic strategy for hepatic fibrosis.