Activation of hepatocyte cannabinoid receptor-1 (CB1R) 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 CB1R-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 CB1R-mediated alcoholic steatosis.

中文翻译：

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肝星状细胞中的谷氨酸信号驱动酒精性脂肪变性。

肝星状细胞（HSC）衍生的2-花生四烯酰甘油（2-AG）对肝细胞大麻素受体1（CB1R）的激活驱动了酒精性肝病（ALD）的新生脂肪形成。酒精如何刺激HSCs中2-AG的产生尚不清楚。在这里，我们报告说，长期饮酒会导致肝半胱氨酸缺乏，并随后通过受损的转硫途径减少谷胱甘肽的消耗。小鼠和ALD患者肝脏中胱氨酸-谷氨酸抗转运蛋白xCT的代偿性增加可提高细胞外谷氨酸水平，并与胱氨酸的摄取相关。酒精还诱导了HSCs中代谢型谷氨酸受体5（mGluR5）的选择性表达，其中mGluR5的激活刺激了2-AG的产生。始终如一 通过抑制2-AG产生和随后CB1R介导的新生脂肪生成，mGluR5或xCT的遗传或药理抑制作用可减轻小鼠的酒精性脂肪变性。我们得出结论，双向信号传导通过xCT介导的谷氨酸-mGluR5信号传导在肝细胞和HSC之间的代谢突触产生2-AG，从而诱导CB1R介导的酒精性脂肪变性。