载脂蛋白H缺乏通过肠道菌群失调和胆汁酸代谢改变加剧酒精性肝损伤。

Apolipoprotein H deficiency exacerbates alcohol-induced liver injury via gut Dysbiosis and altered bile acid metabolism.

作者信息

Liu Yaming, Li Tingting, Xu Jun, Li Shanshan, Li Binbin, Elgozair Mohamad

机构信息

Department of Gastroenterology and Hepatology, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, China 116011; Department of Digestive Diseases, School of Medicine, Xiamen University, Xiamen, Fujian Province, China 361001.

Department of Digestive Diseases, School of Medicine, Xiamen University, Xiamen, Fujian Province, China 361001.

出版信息

Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Oct;1869(7):159535. doi: 10.1016/j.bbalip.2024.159535. Epub 2024 Jul 20.

DOI:10.1016/j.bbalip.2024.159535

PMID:39033850

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.

CONCLUSION

APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.

摘要

背景

载脂蛋白H（APOH）在脂质代谢及循环中脂质的转运过程中发挥着重要作用。既往研究表明，在小鼠模型中，APOH缺乏会导致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机制中的作用及潜在机制仍不清楚。

方法

采用C57BL/6野生型（WT）小鼠和ApoH小鼠构建慢性酒精暴饮喂养模型。对小鼠肝脏转录组、靶向胆汁酸代谢组和16S肠道细菌分类群进行检测和分析。分析开源的人类肝脏转录组数据集。

结果

喂食酒精的ApoH小鼠出现严重的肝脏脂肪变性。肝脏RNA测序和逆转录定量聚合酶链反应（RT-qPCR）数据表明，APOH缺乏主要通过破坏从头脂肪生成、胆固醇加工和胆汁酸代谢来影响肝脏脂质代谢。靶向胆汁酸代谢组学检测表明胆汁酸组成有显著变化，包括喂食酒精的ApoH小鼠肝脏中牛磺胆酸（TCA）百分比增加以及肠道中脱氧胆酸（DCA）百分比增加。与对照小鼠相比，喂食乙醇饮食的ApoH小鼠肝脏中胆酸（CA）、去氧胆酸（NorCA）和石胆酸（HCA）的浓度更高（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相关。最后，来自人类酒精性肝病肝脏的开源转录水平数据突出了APOH下调与脂肪性肝炎以及胆汁酸代谢之间的显著联系。