First Author | Choi WM | Year | 2019 |
Journal | Cell Metab | Volume | 30 |
Issue | 5 | Pages | 877-889.e7 |
PubMed ID | 31474565 | Mgi Jnum | J:281556 |
Mgi Id | MGI:6376953 | Doi | 10.1016/j.cmet.2019.08.001 |
Citation | Choi WM, et al. (2019) Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis. Cell Metab 30(5):877-889.e7 |
abstractText | 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. |