Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
Hepatol Commun. 2023 Apr 26;7(5). doi: 10.1097/HC9.0000000000000138. eCollection 2023 May 1.
Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury.
Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways.
Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet.
Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.
酒精性肝病（ALD）是由慢性饮酒引起的，其范围从肝脂肪变性到纤维化和肝硬化。胆汁酸是生理清洁剂，通过与几种受体结合来调节肝脏的葡萄糖和脂质稳态。其中一种受体，Takeda G 蛋白偶联受体 5（TGR5），可能是治疗 ALD 的一个靶点。在这里，我们使用慢性 10 天+ binge 乙醇喂养模型在小鼠中研究 TGR5 在酒精性肝损伤中的作用。
雌性 C57BL/6J 野生型小鼠和 Tgr5-/- 小鼠接受 Lieber-DeCarli 液体饮食，分别用 5%（v/v）乙醇或等热量对照饮食喂养 10 天，然后分别用 5%乙醇或等热量麦芽糖对照灌胃，代表 binge 饮酒期。 binge 后 9 小时收获组织，通过检查肝脏、脂肪和大脑的机制途径来描述代谢表型。
Tgr5-/- 小鼠免受酒精诱导的肝甘油三酯积累。有趣的是，在 Tgr5-/- 小鼠的乙醇喂养期间，肝和血清 Fgf21 水平显著升高，Stat3 磷酸化也升高。与 Fgf21 水平平行，在 Tgr5-/- 小鼠的乙醇饮食中检测到白色脂肪组织中瘦素基因表达增加和肝脏中瘦素受体增加。Tgr5-/- 小鼠无论饮食如何，脂肪酶基因表达均显著增加，而在乙醇喂养的 Tgr5-/- 小鼠中，脂肪棕色标记物也增加，表明白色脂肪代谢增强。最后，在 Tgr5-/- 小鼠的乙醇饮食中，参与调节食物摄入的瘦素的下丘脑 mRNA 靶标显著增加。
Tgr5-/- 小鼠免受乙醇引起的肝损伤和脂质积累。脂质摄取和 Fgf21 信号的改变，以及白色脂肪组织代谢活性的增强，可能介导这些效应。
