Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation

高氨血症 脂肪生成 酒精性肝病 内科学 内分泌学 脂肪变性 失调 化学 肠道菌群 尿素循环 生物 脂质代谢 生物化学 医学 肝硬化 氨基酸 精氨酸
作者
Qing Song,Chueh‐Lung Hwang,Yanhui Li,Jun Wang,Jooman Park,Samuel M. Lee,Zhaoli Sun,Jun Sun,Yinglin Xia,Natalia Nieto,José Córdoba‐Chacón,Yuwei Jiang,Xiaobing Dou,Zhenyuan Song
出处
期刊:Metabolism-clinical and Experimental [Elsevier]
卷期号:151: 155740-155740 被引量:2
标识
DOI:10.1016/j.metabol.2023.155740
摘要

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 (NH4Cl 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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
shichengLang发布了新的文献求助10
刚刚
优雅雅绿完成签到 ,获得积分10
1秒前
星辰大海应助安可瓶子采纳,获得10
3秒前
Mikasaaaaa完成签到,获得积分10
5秒前
qqqq22完成签到,获得积分10
7秒前
10秒前
10秒前
66完成签到,获得积分20
11秒前
13秒前
14秒前
掌心发布了新的文献求助10
15秒前
16秒前
16秒前
酷波er应助九月三日采纳,获得10
17秒前
17秒前
panting发布了新的文献求助10
18秒前
19秒前
不懈奋进应助kieerw采纳,获得30
19秒前
研友_nPxRRn发布了新的文献求助10
20秒前
wwwwwnnnnn发布了新的文献求助10
22秒前
22秒前
麻烦~发布了新的文献求助30
25秒前
木南发布了新的文献求助10
25秒前
27秒前
东北三省完成签到,获得积分10
27秒前
27秒前
jackbauer发布了新的文献求助10
27秒前
暮霭沉沉应助胡楠采纳,获得10
28秒前
危机的道天关注了科研通微信公众号
29秒前
852应助科研通管家采纳,获得10
29秒前
Akim应助科研通管家采纳,获得10
29秒前
科研通AI2S应助科研通管家采纳,获得10
29秒前
科研通AI2S应助科研通管家采纳,获得10
30秒前
完美世界应助科研通管家采纳,获得30
30秒前
加湿器应助科研通管家采纳,获得200
30秒前
斯文败类应助科研通管家采纳,获得10
30秒前
FashionBoy应助科研通管家采纳,获得10
30秒前
30秒前
掌心完成签到,获得积分10
30秒前
30秒前
高分求助中
Evolution 10000
Sustainability in Tides Chemistry 2800
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
Diagnostic immunohistochemistry : theranostic and genomic applications 6th Edition 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3155733
求助须知:如何正确求助?哪些是违规求助? 2806988
关于积分的说明 7871273
捐赠科研通 2465265
什么是DOI,文献DOI怎么找? 1312193
科研通“疑难数据库(出版商)”最低求助积分说明 629928
版权声明 601892