Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
Drug Clinical Trial Institution, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, China.
Phytomedicine. 2021 Sep;90:153629. doi: 10.1016/j.phymed.2021.153629. Epub 2021 Jun 17.
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.
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.
The alcoholic liver disease model induced by Lieber-Decarli liquid diet was established with or without Yan treatment.
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.
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 β-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-1β and TNF-α expression. Notably, the protective effects of YAN were cancelled by FXR siRNA in vitro and FXR antagonist GS in vivo.
YAN exerted significant hepatoprotective effects against liver injury triggered by ethanol via FXR-mediated target gene modulation.
酒精性肝病（ALD）是一种进行性疾病，从单纯性脂肪变性开始，但可进展为酒精性肝炎、纤维化、肝硬化，甚至肝细胞癌。ALD 的发病率正在上升，已成为全球医疗保健系统的沉重负担。不幸的是，目前尚无针对 ALD 的批准治疗药物。因此，开发有效的治疗方法迫在眉睫。许多针对 ALD 的分子靶标的作用能力正在研究中。法尼醇 X 受体（FXR）是配体激活转录因子超家族的成员，最近已被证明在 ALD 的发病机制和进展中起关键作用。
本研究旨在确定我们之前证明的 FXR 激动剂羊齿宁（YAN）是否对 ALD 具有肝保护作用，并进一步阐明其在体内和体外的作用机制。
采用 Lieber-Decarli 液体饮食建立酒精性肝病模型，并进行 YAN 治疗。
测定肝体比、体重、血清和肝生化指标。通过 H&E 和免疫组化染色评估肝组织病理学进展的缓解情况。采用 Western blot 和实时定量 PCR 显示 YAN 治疗 ALD 的缓解机制。
数据表明，YAN 通过激活 FXR 对 ALD 具有肝保护活性。YAN 通过调节相关蛋白，降低肝内脂质生成，增加脂肪酸β氧化和脂蛋白脂肪酶活性，改善脂质稳态。此外，YAN 通过抑制胆汁酸摄取转运体 Ntcp 并诱导胆汁酸外排转运体 Bsep 和 Mrp2 表达，改善乙醇诱导的胆汁淤积。此外，YAN 通过诱导 Sult2a1 表达和抑制 Cyp7a1 和 Cyp8b1 表达，改善胆汁酸稳态。此外，YAN 通过抑制细胞衰老标志物 P16、P21 和 Hmga1 表达，减轻乙醇引发的肝细胞损伤。此外，YAN 通过下调炎症相关基因 IL-6、IL-1β 和 TNF-α 的表达，减轻乙醇诱导的炎症。值得注意的是，体外 FXR siRNA 和体内 FXR 拮抗剂 GS 可消除 YAN 的保护作用。
YAN 通过 FXR 介导的靶基因调节，对乙醇引起的肝损伤发挥显著的肝保护作用。
