肠道来源的氨通过促进乙醇代谢和激活ATF4依赖的从头脂肪生成，促进酒精性脂肪肝的发展。
Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation.
作者信息
Song Qing, Hwang Chueh-Lung, Li Yanhui, Wang Jun, Park Jooman, Lee Samuel M, Sun Zhaoli, Sun Jun, Xia Yinglin, Nieto Natalia, Cordoba-Chacon Jose, Jiang Yuwei, Dou Xiaobing, Song Zhenyuan
机构信息
Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA.
Department of Kinesiology, University of Texas at Arlington, Arlington, TX, USA.
出版信息
Metabolism. 2024 Feb;151:155740. doi: 10.1016/j.metabol.2023.155740. Epub 2023 Nov 22.
BACKGROUND & AIMS: Dysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD.
METHODS
Blood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NHCl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of enzymes involved in multiple pathways were measured.
RESULTS
Chronic alcohol consumption causes hyperammonemia in both mice and human subjects. In healthy livers and hepatocytes, ammonia exposure upregulates the expression of urea cycle genes, elevates hepatic de novo lipogenesis (DNL), and increases fat accumulation. Intriguingly, ammonia promotes ethanol catabolism and acetyl-CoA formation, which, together with ammonia, synergistically facilitates intracellular fat accumulation in hepatocytes. Mechanistic investigations uncovered that ATF4 activation, as a result of ER stress induction and general control nonderepressible 2 activation, plays a central role in ammonia-provoked DNL elevation. Rifaximin ameliorates ALD pathologies in mice, concomitant with blunted hepatic ER stress induction, ATF4 activation, and DNL activation.
CONCLUSIONS
An overproduction of ammonia by gut microbiota, synergistically interacting with ethanol, is a significant contributor to ALD pathologies.
背景与目的
肠道菌群失调与酒精性肝病（ALD）的发生发展相关，但其确切机制仍不清楚。鉴于肠道微生物群在氨生成中起关键作用，我们旨在研究肠道来源的氨是否以及如何导致ALD。
方法
采集有/无饮酒习惯的人类受试者的血液样本。将小鼠分为四组，分别给予Lieber-DeCarli等热量对照饮食、含乙醇饮食、含乙醇且补充利福昔明（一种临床上用于降低肠道氨生成的非吸收性抗生素）的饮食、含乙醇且补充利福昔明的饮食，持续五周。采用体外（AML12肝细胞暴露于氯化铵）和体内（给小鼠注射尿素酶5天）高氨血症模型。进行RNA测序和粪便扩增子测序。测定氨和甘油三酯浓度。检测参与多种途径的酶的基因和蛋白表达。
结果
长期饮酒会导致小鼠和人类受试者出现高氨血症。在健康肝脏和肝细胞中，氨暴露会上调尿素循环基因的表达，增加肝脏从头脂肪生成（DNL），并增加脂肪积累。有趣的是，氨促进乙醇分解代谢和乙酰辅酶A的形成，二者与氨协同作用，促进肝细胞内脂肪积累。机制研究发现，内质网应激诱导和一般控制非抑制性2激活导致的激活转录因子4（ATF4）激活在氨诱导的DNL升高过程中起核心作用。利福昔明可改善小鼠的ALD病理状况，同时减轻肝脏内质网应激诱导、ATF4激活和DNL激活。
结论
肠道微生物群产生的氨过量与乙醇协同作用，是ALD病理变化的一个重要因素。
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