Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Alcohol Clin Exp Res. 2021 Oct;45(10):1980-1993. doi: 10.1111/acer.14700. Epub 2021 Sep 29.
Mouse models of alcohol-associated liver disease vary greatly in their ease of implementation and the pathology they produce. Effects range from steatosis and mild inflammation with the Lieber-DeCarli liquid diet to severe inflammation, fibrosis, and pyroptosis seen with the Tsukamoto-French intragastric feeding model. Implementation of all of these models is limited by the labor-intensive nature of the protocols and the specialized skills necessary for successful intragastric feeding. We thus sought to develop a new model to reproduce features of alcohol-induced inflammation and fibrosis with minimal operational requirements.
Over a 16-week period, mice were fed ad libitum with a pelleted high-fat Western diet (WD; 40% calories from fat) and alcohol added to the drinking water. We found the optimal alcohol consumption to be that at which the alcohol concentration was 20% for 4 days and 10% for 3 days per week. Control mice received WD pellets with water alone.
Alcohol consumption was 18 to 20 g/kg/day in males and 20 to 22 g/kg/day in females. Mice in the alcohol groups developed elevated serum transaminase levels after 12 weeks in males and 10 weeks in females. At 16 weeks, both males and females developed liver inflammation, steatosis, and pericellular fibrosis. Control mice on WD without alcohol had mild steatosis only. Alcohol-fed mice showed reduced HNF4α mRNA and protein expression. HNF4α is a master regulator of hepatocyte differentiation, down-regulation of which is a known driver of hepatocellular failure in alcoholic hepatitis.
A simple-to-administer, 16-week WD alcohol model recapitulates the inflammatory, fibrotic, and gene expression aspects of human alcohol-associated steatohepatitis.
酒精相关性肝病的小鼠模型在实施难度和产生的病理学方面差异很大。从 Lieber-DeCarli 液体饮食引起的脂肪变性和轻度炎症到 Tsukamoto-French 胃内喂养模型引起的严重炎症、纤维化和焦亡，效果各异。所有这些模型的实施都受到协议的劳动密集性质和成功胃内喂养所需的专业技能的限制。因此，我们试图开发一种新的模型，以最小的操作要求再现酒精引起的炎症和纤维化的特征。
在 16 周的时间里，小鼠自由摄食高脂肪西方饮食（WD；40%的热量来自脂肪），并在饮用水中添加酒精。我们发现最佳的酒精摄入量是每周 4 天摄入 20%的酒精，3 天摄入 10%的酒精。对照组小鼠仅用 WD 颗粒喂养。
雄性小鼠的酒精摄入量为 18 至 20 克/公斤/天，雌性小鼠的酒精摄入量为 20 至 22 克/公斤/天。酒精组的小鼠在雄性 12 周和雌性 10 周后血清转氨酶水平升高。在 16 周时，雄性和雌性小鼠均出现肝脏炎症、脂肪变性和细胞周围纤维化。未饮酒的 WD 对照组小鼠仅出现轻度脂肪变性。酒精喂养的小鼠表现出 HNF4α mRNA 和蛋白表达降低。HNF4α 是肝细胞分化的主要调节因子，其下调是酒精性肝炎中肝细胞衰竭的已知驱动因素。
一种简单易实施的 16 周 WD 酒精模型再现了人类酒精相关性脂肪性肝炎的炎症、纤维化和基因表达方面。
