| Paracrine activation of hepatocyte CB1R by hepatic stellate cell (HSC)-derived 2-arachidonoylglycerol (2-AG) contributes to alcoholic steatosis by stimulating de novo lipogenesis in hepatocytes. However, the mechanism by which alcohol stimulates 2-AG production in HSCs is unknown. Mice were fed 5% liquid ethanol diet for 8 weeks. At sacrifice, blood, liver tissues and hepatic cells of mice were collected. To investigate the roles of mGluR5 and xCT, genetic and pharmacologic inhibitions were subjected to the mice. Blood and biopsy samples of liver tissues from patients with alcoholic liver disease were collected for further analyses. Here, we report that chronic alcohol consumption significantly increased plasma glutamate levels both in mice and in patients. RNA-Seq analysis revealed the upregulation of hepatic cystine-glutamate antiporter xCT through the antioxidant transcription factor Nrf2 in ethanol-fed mice. Ethanol feeding induced hepatic cysteine deficiency and subsequent glutathione depletion by impaired transsulfuration pathway. A compensatory increase in hepatic xCT resulted in glutamate excretion coupled to cystine uptake. Alcohol also induced the selective expression of the metabotropic glutamate receptor mGluR5 in HSCs, and mGluR5 activation stimulated 2-AG production. Consistently, genetic deletion or pharmacologic inhibition of mGluR5 or xCT attenuated alcoholic steatosis in mice via suppression of 2-AG production and de novo lipogenesis. We conclude that alcohol-induced upregulation of xCT results in increased excretion of hepatic glutamate, which triggers mGluR5-mediated 2-AG production in HSCs, a pathway that could be targeted for the treatment of alcoholic fatty liver disease. |
