METHODS: C57BL/6 WT and ApoH-/- mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed.
RESULTS: ApoH-/- mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH-/- mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH-/- mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism.
CONCLUSIONS: APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.
方法:用C57BL/6WT和ApoH-/-小鼠构建长期酗酒模型。小鼠肝脏转录组,靶向胆汁酸代谢组,和16S肠道细菌分类群进行了测定和分析。分析开源人类肝脏转录组数据集。
结果:酒精喂养的ApoH-/-小鼠表现出严重的肝性脂肪变性。肝脏RNAseq和RT-qPCR数据表明,APOH缺乏主要通过破坏从头脂肪生成影响肝脂质代谢,胆固醇处理,和胆汁酸代谢。有针对性的胆汁酸代谢组学测定表明胆汁酸成分发生了显着变化,包括酒精喂养的ApoH-/-小鼠肝脏中TCA和肠道中DCA的百分比增加。CA的浓度,NorCA,与对照小鼠相比,乙醇饮食的ApoH-/-小鼠的肝脏中的HCA更高(p<0.05)。此外,APOH缺乏改变了肠道菌群的组成,这与乙醇喂养小鼠模型中肝脏胆汁酸组成的变化有关。最后,来自人类ALD肝脏的开源转录水平数据强调了APOH下调和脂肪性肝炎之间的显着联系,以及胆汁酸代谢。
结论:APOH缺乏通过破坏小鼠肠道菌群稳态和胆汁酸代谢,加重酒精诱导的肝脂肪变性。