Yohimbine Ameliorates Liver Inflammation and Fibrosis by Regulating Oxidative Stress and Wnt/β-catenin Pathway.

Background and purpose: Chronic 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. Methods: To assess the anti-inflammatory, antioxidant, and anti-fibrotic effects of YHC, lipopolysaccharide or TGF-beta 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. Results: Inflammation/differentiation experiments in HLECs and HSC-LX2 revealed that YHC treatment significantly (p < 0.001) mitigated the lipopolysaccharide or TGF-beta induced upregulation of inflammatory and fibrotic markers expression respectively. In addition, YHC dose-dependently reduced the TGF-beta 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 beta-catenin expression in hepatic stellate cells and animal tissues. Further treatment with YHC significantly modulated the JNK/Wnt/beta-catenin signaling. Moreover, the beta-catenin nuclear translocation results showed that beta-catenin levels were significantly elevated in the nuclear fraction of TAA control samples and reduced in YHC-treated samples. Conclusion: Yohimbine treatment significantly improved inflammation and fibrosis by inhibiting differentiation, oxidative stress, and collagen deposition by partly modulating the JNK/Wnt/beta-catenin pathway. These results might serve as a foundation for proposing yohimbine as a potential lead compound for liver fibrosis.