Glutamate/metabotropic glutamate receptor-5 signaling in hepatic stellate cells drives endocannabinoid-mediated alcoholic steatosis

• Published in: Cell metabolism 2019-08, Vol.30 (5), p.877-889.e7
• Main Authors: Choi, Won-Mook, Kim, Hee-Hoon, Kim, Myung-Ho, Cinar, Resat, Yi, Hyon-Seung, Eun, Hyuk Soo, Kim, Seok-Hwan, Choi, Young Jae, Lee, Young-Sun, Kim, So Yeon, Seo, Wonhyo, Lee, Jun-Hee, Shim, Young-Ri, Kim, Ye Eun, Yang, Keungmo, Ryu, Tom, Hwang, Jung Hwan, Lee, Chul-Ho, Choi, Hueng-Sik, Gao, Bin, Kim, Won, Kim, Sang Kyum, Kunos, George, Jeong, Won-Il
• Format: Article
• Language: English
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.08.001

Activation of hepatocyte cannabinoid receptor-1 (CB 1 R) 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 antiporter 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 suppression of 2-AG production and subsequent CB 1 R-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 1 R-mediated alcoholic steatosis. Choi et al. show that chronic alcohol consumption induces CYP2E1-mediated ROS production by hepatocytes, which is compensated by GSH generation through xCT-mediated uptake of cystine. The parallel release of glutamate stimulates mGluR5 on hepatic stellate cells (HSCs) to produce 2-AG which, in turn, activates CB-iR on neighboring hepatocytes to induce de novo lipogenesis.