期刊
CELL METABOLISM
卷 30, 期 5, 页码 877-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.08.001
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资金
- National Research Foundation of Korea (NRF) - Korea government (MEST) [2018R1A2A1A05077608]
- Korea Mouse Phenotyping Project [2014M3A9D5A01073556]
- Intelligent Synthetic Biology Center of Global Frontier Project [2011-0031955]
- Global Ph.D. Fellowship program through the National Research Foundation (NRF) of Korea - Ministry of Science, ICT and future Planning [NRF-2015H1A2A1033124]
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
- National Research Foundation of Korea [2018R1A2A1A05077608] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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