The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease.
The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease.
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DOI：
10.1002/hep4.1793
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发表时间：
2022-01
影响因子：
5.1
通讯作者：
Nieto N
中科院分区：
文献类型：
--
作者：
Das S;Ge X;Han H;Desert R;Song Z;Athavale D;Chen W;Gaskell H;Lantvit D;Guzman G;Nieto N
酒精相关性肝病（ALD）是一个重要的临床问题，最有效的治疗方法是戒酒。本研究的两个目的是，首先，确定在损伤高峰期以及ALD早期和晚期消退期间的肝脏转录组，粪便微生物组和门静脉血清代谢组;其次，整合它们的相互作用并更好地了解ALD的发病机制。为了引起酒精诱导的肝损伤，雌性和雄性野生型小鼠喂食对照或乙醇Lieber-DeCarli饮食6周。为了研究早期和晚期消退，从饮食中撤出酒精，并分别在3天和14天后处死小鼠。在峰值损伤时，信号转导和转录激活因子（Stat 3）、Rho-GTP酶、Tec激酶和糖蛋白VI（Gp 6）增加，过氧化物酶体增殖物激活受体信号传导减少。在ALD消退期间，维生素D受体/维甲酸X受体、toll样受体、p38和Stat 3上调，肝脏X受体信号转导下调。雌性动物的分解代谢途径发生了显著变化，而雄性动物的细胞应激、损伤和免疫反应途径增加，这些途径在消退期间减少。在两种性别中，细菌属Alistipes和代谢产物二肽甘氨酰-L-亮氨酸在峰值时增加，但在ALD消退期间减少。肝脏对丝裂原活化蛋白激酶（Map 3 k1）的诱导与峰值时微生物组和代谢组的变化相关，但在ALD消退期间恢复。MAP 3 K1的抑制保护小鼠免受ALD。结论：酒精戒断以性别特异性方式恢复肝脏转录组，粪便微生物组和门静脉血清代谢组。多组学数据的整合将Map 3 k1确定为驱动ALD发病机制和解决的关键基因。抑制MAP 3 K1活性可预防酒精诱导的肝损伤。
Alcohol‐associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol‐induced liver injury, female and male wild‐type mice were fed the control or ethanol Lieber‐DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho‐GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator–activated receptor signaling. During resolution from ALD, there was up‐regulation of vitamin D receptor/retinoid X receptor, toll‐like receptor, p38 and Stat3, and down‐regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune‐response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl‐L‐leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen‐activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender‐specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD. Inhibition of MAP3K1 activity prevents alcohol‐induced liver injury.
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DOI：
10.1002/hep.30093
发表时间：
2018-12
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ge X;Arriazu E;Magdaleno F;Antoine DJ;Dela Cruz R;Theise N;Nieto N
通讯作者：
Nieto N
影响因子：
29.4
作者：
Betrapally NS;Gillevet PM;Bajaj JS
通讯作者：
Bajaj JS
影响因子：
13.5
作者：
Ge, Xiaodong;Leung, Tung-Ming;Arriazu, Elena;Lu, Yongke;Urtasun, Raquel;Christensen, Brian;Fiel, Maria Isabel;Mochida, Satoshi;Sorensen, Esben S.;Nieto, Natalia
通讯作者：
Nieto, Natalia
影响因子：
24.5
作者：
Arriazu E;Ge X;Leung TM;Magdaleno F;Lopategi A;Lu Y;Kitamura N;Urtasun R;Theise N;Antoine DJ;Nieto N
通讯作者：
Nieto N
影响因子：
3.7
作者：
Beier JI;McClain CJ
通讯作者：
McClain CJ