β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway.
β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway.
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DOI：
10.1016/j.jhep.2018.04.004
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发表时间：
2018-09
影响因子：
25.7
通讯作者：
Mehal WZ
中科院分区：
文献类型：
--
作者：
Chen Y;Ouyang X;Hoque R;Garcia-Martinez I;Yousaf MN;Tonack S;Offermanns S;Dubuquoy L;Louvet A;Mathurin P;Massey V;Schnabl B;Bataller RA;Mehal WZ
无菌性炎症导致酒精性肝炎（AH）在多年过量饮酒后不可预测地发生。导致AH发生的因素尚不清楚，但线粒体损伤和线粒体功能丧失是AH的共同特征。Hcar2是一种g蛋白偶联受体，可被β-羟基丁酸酯（BHB）激活，BHB-Hcar2通路与酒精性肝病的相关性尚不清楚。我们测试了BHB分泌减少是否会导致肝脏炎症增加。我们进一步测试了BHB补充剂是否可以通过与Hcar2的相互作用来保护AH，以及保护的免疫和细胞基础。患有AH的人肝脏BHB减少，抑制小鼠BHB的产生加重了乙醇诱导的AH，血清ALT水平升高，脂肪变性增加，中性粒细胞内流增加。相反，补充BHB对降低ALT水平、减少脂肪变性和中性粒细胞内流具有相反的作用。BHB的这种治疗效果依赖于受体Hcar2。BHB处理增加了肝脏IL-10转录，促进了肝内巨噬细胞的M2表型。BHB还增加了骨髓源性巨噬细胞中M2相关基因的转录水平。这种向M2相关基因的倾斜取决于BHB诱导的较低的线粒体膜电位（Δψ）。总的来说，我们的数据表明过量饮酒时产生的BHB通过Hcar2依赖途径具有抗炎和保护肝脏的作用，并引入了基于代谢物治疗AH的概念。
Sterile inflammation resulting in alcohol hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by β-hydroxybutyrate (BHB), and the relevance of the BHB-Hcar2 pathway in alcoholic liver disease is not known. We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation can protect in AH through interaction with Hcar2, and the immune and cellular basis for protection. Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol induced AH, with higher serum ALT levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced ALT levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver IL-10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (Δψ) induced by BHB. Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through a Hcar2 dependent pathway, and introduces the concept of metabolite based therapy for AH.
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DOI：
10.1161/atvbaha.116.307573
发表时间：
2016-07
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Lin J;Hu Y;Nunez S;Foulkes AS;Cieply B;Xue C;Gerelus M;Li W;Zhang H;Rader DJ;Musunuru K;Li M;Reilly MP
通讯作者：
Reilly MP
影响因子：
2.2
作者：
Elliott, Simon;Smith, Christopher;Cassidy, Diane
通讯作者：
Cassidy, Diane
DOI：
10.1016/j.metabol.2014.11.007
发表时间：
2015-03
期刊：
Metabolism: clinical and experimental
影响因子：
--
作者：
Frisard MI;Wu Y;McMillan RP;Voelker KA;Wahlberg KA;Anderson AS;Boutagy N;Resendes K;Ravussin E;Hulver MW
通讯作者：
Hulver MW
影响因子：
13.5
作者：
Mandrekar, Pranoti;Bataller, Ramon;Tsukamoto, Hidekazu;Gao, Bin
通讯作者：
Gao, Bin
影响因子：
6.5
作者：
Clugston, Robin D.;Jiang, Hongfeng;Blaner, William S.
通讯作者：
Blaner, William S.