Yohimbine ameliorates liver inflammation and fibrosis by regulating oxidative stress and Wnt/β-catenin pathway

Abstract

Background and purposeChronic liver injury, caused by various aetiologies, causes recurrent tissue damage, culminating in decreased liver regenerative ability and resulting in fibrosis followed by cirrhosis. In this study, the anti-fibrotic activity of Yohimbine hydrochloride (YHC) was investigated using various in vitro models and in vivo models. MethodsTo assess the anti-inflammatory, antioxidant, and anti-fibrotic effects of YHC, lipopolysaccharide or TGF-β induced differentiation or lipid-induced oxidative-stress models were employed using HLECs, HSC-LX2, and HepG2 cells. Further, thioacetamide (TAA) induced hepatic inflammation/fibrosis models were utilized to validate the YHC's anti-fibrotic activity in rats. ResultsInflammation/differentiation experiments in HLECs and HSC-LX2 revealed that YHC treatment significantly (p < 0.001) mitigated the lipopolysaccharide or TGF-β induced upregulation of inflammatory and fibrotic markers expression respectively. In addition, YHC dose-dependently reduced the TGF-β induced migration and palmitic acid-induced oxidative stress in HepG2 cells. Further, TAA administration (5 weeks) in vivo rat model showed increased inflammatory marker levels/expression, oxidative stress, and pathological abnormalities. Additionally, TAA administration (9 weeks) elevated the fibrotic marker expression, collagen deposition in liver tissues, and shortened longevity in rats. Treatment with YHC dose-dependently mitigated the TAA-induced abnormalities in both inflammation and fibrosis models and improved the survival of the rats. Further mechanistic approaches revealed that TAA administration elevated the JNK, Wnt components and β-catenin expression in hepatic stellate cells and animal tissues. Further treatment with YHC significantly modulated the JNK/Wnt/β-catenin signaling. Moreover, the β-catenin nuclear translocation results showed that β-catenin levels were significantly elevated in the nuclear fraction of TAA control samples and reduced in YHC-treated samples. ConclusionYohimbine treatment significantly improved inflammation and fibrosis by inhibiting differentiation, oxidative stress, and collagen deposition by partly modulating the JNK/Wnt/β-catenin pathway. These results might serve as a foundation for proposing yohimbine as a potential lead compound for liver fibrosis.