韩国科学技术学院Won-Il Jeong和美国国立卫生研究院George Kunos团队研究发现，肝星状细胞内谷氨酸信号转导导致酒精性脂肪肝。相关论文2019年8月29日在线发表于《细胞—代谢》上。
研究发现慢性酒精消耗导致肝脏半胱氨酸缺乏，以及因转硫途径受损而导致的谷胱甘肽耗竭。使用肝脏胱氨酸—谷氨酸转运通道蛋白抑制剂xCT可以恢复小鼠和ALD患者细胞外谷氨酸水平与胱氨酸摄取。酒精还诱导HSC中代谢型谷氨酸受体-5（mGluR5）的选择性表达，并且mGluR5激活刺激2-AG产生。与此同时，利用遗传手段或药物抑制mGluR5或xC可以抑制2-AG的产生和CB1R介导的脂肪从头合成从而减弱小鼠酒精性脂肪变性。研究人员证实，双向信号通过 xCT介导的谷氨酸-mGluR5信号传导在肝细胞和HSC之间的代谢中起作用以产生2-AG，其诱导CB1R介导的酒精性脂肪变性。
研究人员介绍，肝星状细胞（HSC）产生的2-花生四烯酸甘油酯（2-AG）激活肝细胞大麻素受体-1（CB1R）驱动酒精性肝病（ALD）患者体内脂肪的从头合成。但是酒精如何促进HSC中2-AG的产生尚不清楚。
附：英文原文
Title: Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis
Author: Won-Mook Choi, Hee-Hoon Kim, Myung-Ho Kim, Resat Cinar, Hyon-Seung Yi, Hyuk Soo Eun, Seok-Hwan Kim, Young Jae Choi, Young-Sun Lee, So Yeon Kim, Wonhyo Seo, Jun-Hee Lee, Young-Ri Shim, Ye Eun Kim, Keungmo Yang, Tom Ryu, Jung Hwan Hwang, Chul-Ho Lee, Hueng-Sik Choi, Bin Gao, Won Kim, Sang Kyum Kim, George Kunos, Won-Il Jeong
Issue&Volume: 29 August 2019
Abstract: Activation of hepatocyte cannabinoid receptor-1 (CB 1R) by hepatic stellate cell (HSC)-derived 2-arachidonoylglycerol (2-AG) drives de novo lipogenesis in alcoholic liver disease (ALD). How alcohol stimulates 2-AG production in HSCs is unknown. Here, we report that chronic alcohol consumption induced hepatic cysteine deficiency and subsequent glutathione depletion by impaired transsulfuration pathway. A compensatory increase in hepatic cystine-glutamate anti-porter xCT boosted extracellular glutamate levels coupled to cystine uptake both in mice and in patients with ALD. Alcohol also induced the selective expression of metabotropic glutamate receptor-5 (mGluR5) in HSCs where mGluR5 activation stimulated 2-AG production. Consistently, genetic or pharmacologic inhibition of mGluR5 or xCT attenuated alcoholic steatosis in mice via the suppression of 2-AG production and subsequent CB 1R-mediated de novo lipogenesis. We conclude that a bidirectional signaling operates at a metabolic synapse between hepatocytes and HSCs through xCT-mediated glutamate-mGluR5 signaling to produce 2-AG, which induces CB 1R-mediated alcoholic steatosis.
DOI: https://doi.org/10.1016/j.cmet.2019.08.001
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30430-9#
Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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本期文章：《细胞—代谢》：Online/在线发表
