Abstract：
BACKGROUND: APOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear.
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.
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.
摘要：
背景：APOH在脂质代谢和脂质在循环中的运输中起着至关重要的作用。先前的研究表明，APOH缺乏会导致小鼠模型中的脂肪肝和肠道微生物群失调。然而,APOH缺乏在酒精性肝病发病中的作用和潜在机制尚不清楚.
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。
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。
