4.7 Article

Yangonin modulates lipid homeostasis, ameliorates cholestasis and cellular senescence in alcoholic liver disease via activating nuclear receptor FXR

期刊

PHYTOMEDICINE
卷 90, 期 -, 页码 -

出版社

ELSEVIER GMBH
DOI: 10.1016/j.phymed.2021.153629

关键词

Alcoholic liver injury; Farnesoid X receptor; Yangonin; Lipid homeostasis; Cellular senescence

资金

  1. National Natural Science Foundation of China [81302826, 81874324]
  2. Dalian Science, technology innovation fund [2018J12SN065]
  3. Basic research project of Education Department of Liaoning Province [LZ2019037]
  4. Project of Liaoning BaiQianWan Talents Program

向作者/读者索取更多资源

The study aimed to investigate whether the FXR agonist Yangonin (YAN) exerted hepatoprotective effects against ALD, and elucidate the mechanisms in vitro and in vivo. Results showed that YAN activated FXR to improve lipid homeostasis, alleviate liver histopathological progression, reduce ethanol-induced cholestasis, improve bile acid homeostasis, and attenuate hepatocyte damage and inflammation. These protective effects were demonstrated to be mediated by FXR-regulated target gene modulation.
Background: : Alcoholic liver disease (ALD) is a progressive disease beginning with simple steatosis but can progress to alcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. The morbidity of ALD is on the rise and has been a large burden on global healthcare system. It is unfortunately that there are currently no approved therapeutic drugs against ALD. Hence, it is of utmost urgency to develop the efficacious therapies. The ability of many molecular targets against ALD is under investigation. Farnesoid X receptor (FXR), a member of the ligand-activated transcription factor superfamily, has been recently demonstrated to have a crucial role in the pathogenesis and progression of ALD. Purpose: : The purpose of the study is to determine whether Yangonin (YAN), a FXR agonist previously demonstrated by us, exerts the hepatoprotective effects against ALD and further to clarify the mechanisms in vitro and in vivo. Study design: : The alcoholic liver disease model induced by Lieber-Decarli liquid diet was established with or without Yan treatment. Methods: : We determined the liver to body weight ratios, the body weight, serum and hepatic biochemical indicators. The alleviation of the liver histopathological progression was evaluated by H&E and immunohistochemical staining. Western blot and quantitative real-time PCR were used to demonstrate YAN treatment-mediated alleviation mechanisms of ALD. Results: : The data indicated that YAN existed hepatoprotective activity against ALD via FXR activation. YAN improved the lipid homeostasis by decreasing hepatic lipogenesis and increasing fatty acid beta-oxidation and lipoprotein lipolysis through modulating the related protein. Also, YAN ameliorated ethanol-induced cholestasis via inhibiting bile acid uptake transporter Ntcp and inducing bile acid efflux transporter Bsep and Mrp2 expression. Besides, YAN improved bile acid homeostasis via inducing Sult2a1 expression and inhibiting Cyp7a1 and Cyp8b1 expression. Furthermore, YAN attenuated ethanol-triggered hepatocyte damage by inhibiting cellular senescence marker P16, P21 and Hmga1 expression. Also, YAN alleviated ethanol-induced inflammation by down-regulating the inflammation-related gene IL-6, IL-1 beta and TNF-alpha expression. Notably, the protective effects of YAN were cancelled by FXR siRNA in vitro and FXR antagonist GS in vivo. Conclusions: : YAN exerted significant hepatoprotective effects against liver injury triggered by ethanol via FXR-mediated target gene modulation.

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