Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis
Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis
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DOI：
10.1016/j.cmet.2019.08.001
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发表时间：
2019-11-05
期刊：
影响因子：
29
通讯作者：
Jeong, Won-Il
中科院分区：
文献类型：
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作者：
Choi, Won-Mook;Kim, Hee-Hoon;Jeong, Won-Il
肝星状细胞(HSC)衍生的2-花生四烯酸甘油(2-AG)激活肝细胞大麻素受体-1(CB1R)可促进酒精性肝病(ALD)的新生脂肪生成。酒精是如何刺激HSCs产生2-AG的，目前尚不清楚。在这里，我们报告长期饮酒导致肝脏半胱氨酸缺乏和随后的谷胱甘肽耗竭，这是通过破坏跨硫途径来实现的。在小鼠和ALD患者中，肝脏半胱氨酸-谷氨酸反转运体XCT的代偿性增加提高了细胞外谷氨酸水平，与半胱氨酸摄取有关。酒精还可诱导HSC选择性表达代谢型谷氨酸受体5(MGluR5)，而mGluR5激活可刺激2-AG的产生。一贯地，基因或药物抑制mGluR5或XCT通过抑制2-AG的产生和随后CB1R介导的从头脂肪生成来减轻小鼠的酒精性脂肪变性。我们的结论是，双向信号通过XCT介导的谷氨酸-mGluR5信号作用于肝细胞和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。
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.