Testicular orphan receptor 4 induced hepatic stellate cells activation via the regulation of TGF-β receptor Ⅰ/Smad2/3 signaling pathway

Abstract

Introduction and objectives: Liver fibrosis is a common pathological change in many chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the core event in liver fibrosis. This study aimed to investigate the role of testicular orphan receptor 4 (TR4) in the activation of HSCs.

Materials and methods: In vivo, bile duct ligation (BDL)-induced rat liver fibrosis model was established, and the expressions of TR4 and α-smooth muscle actin (α-SMA) in liver tissues were detected. In vitro, TR4 knockdown and overexpression in JS-1 cells using lentiviral vectors were constructed, and the expressions of TR4, α-SMA, Col-I, and TGF-β1/smads and retinoid X receptor (RXR) pathway-related genes were detected.

Results: TR4 was highly expressed in BDL-induced fibrotic liver, accompanied by increased expression of α-SMA. Knockdown of TR4 significantly inhibited the expressions of α-SMA, Col-I, p-TβRI, and p-Smad2/3, and up-regulated the expression of RXRα in HSCs in vitro. In contrast, TR4 overexpression significantly increased the expressions of α-SMA, Col-I, p-TβRI, and p-Smad2/3, and inhibited the expression of RXRα.

Conclusions: TR4 may promote the activation of HSCs by up-regulating TβR I/Smad2/3 signaling pathway and down-regulating RXRα signaling, thereby promoting the progression of liver fibrosis. Our findings may provide a new therapeutic target against hepatic fibrosis.

Keywords: Hepatic stellate cells; Liver fibrosis; Retinoid X receptor α; TGF-β receptor Ⅰ/Smad2/3; Testicular orphan receptor 4.