There is an increasing need to explore the mechanism of the progression of non-alcoholic fatty liver disease. Steroid metabolism is closely linked to hepatic steatosis and steroids are excreted as bile acids (BAs). Here, we demonstrated that feeding WKAH/HkmSlc inbred rats a diet supplemented with cholic acid (CA) at 0.5 g/kg for 13 weeks induced simple steatosis without obesity. Liver triglyceride and cholesterol levels were increased accompanied by mild elevation of aminotransferase activities. There were no signs of inflammation, insulin resistance, oxidative stress, or fibrosis. CA supplementation increased levels of CA and taurocholic acid (TCA) in enterohepatic circulation and deoxycholic acid (DCA) levels in cecum with an increased ratio of 12α-hydroxylated BAs to non-12α-hydroxylated BAs. Analyses of hepatic gene expression revealed no apparent feedback control of BA and cholesterol biosynthesis. CA feeding induced dysbiosis in cecal microbiota with enrichment of DCA producers, which underlines the increased cecal DCA levels. The mechanism of steatosis was increased expression of Srebp1 (positive regulator of liver lipogenesis) through activation of the liver X receptor by increased oxysterols in the CA-fed rats, especially 4β-hydroxycholesterol (4βOH) formed by upregulated expression of hepatic Cyp3a2, responsible for 4βOH formation. Multiple regression analyses identified portal TCA and cecal DCA as positive predictors for liver 4βOH levels. The possible mechanisms linking these predictors and upregulated expression of Cyp3a2 are discussed. Overall, our observations highlight the role of 12α-hydroxylated BAs in triggering liver lipogenesis and allow us to explore the mechanisms of hepatic steatosis onset, focusing on cholesterol and BA metabolism.

越来越需要探索非酒精性脂肪肝疾病发展的机制。类固醇代谢与肝脂肪变性密切相关，类固醇以胆汁酸（BAs）的形式排出。在这里，我们证明以WKAH / HkmSlc近交大鼠饲喂补充0.5 g / kg胆酸（CA）的饮食13周可以诱发单纯性脂肪变性而无肥胖。肝甘油三酸酯和胆固醇水平升高，同时氨基转移酶活性轻度升高。没有炎症，胰岛素抵抗，氧化应激或纤维化的迹象。补充CA会增加肠肝循环中CA和牛磺胆酸（TCA）的水平以及盲肠中脱氧胆酸（DCA）的水平，增加12α-羟基化BA与非12α-羟基化BA的比例。肝基因表达的分析表明没有明显的反馈控制BA和胆固醇的生物合成。CA饲喂导致盲肠菌群营养不良，DCA生产者数量增加，这突出了盲肠DCA水平的升高。脂肪变性的机制是表达增加Srebp1（肝脂肪生成的正调节剂）通过在CA喂养的大鼠中增加的氧固醇激活肝X受体而激活，特别是由上调负责4βOH形成的肝Cyp3a2表达形成的4β-羟基胆固醇（4βOH）。多元回归分析确定门TCA和盲肠DCA是肝4βOH水平的阳性预测指标。讨论了将这些预测因子与Cyp3a2表达上调的可能机制。总体而言，我们的观察结果突出了12α-羟基化BAs在触发肝脏脂肪形成中的作用，并使我们能够探索肝脂肪变性发作的机制，重点是胆固醇和BA代谢。