Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis
- 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
- Issue Date
- 5-11월-2019
- Publisher
- CELL PRESS
- Keywords
- 2-arachidonoylglycerol; alcoholic liver disease; cannabinoid receptor; metabotrophic glutamate receptor 5; Nrf2; transsulfuration pathway; xCT
- Citation
- CELL METABOLISM, v.30, no.5, pp.877 - +
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELL METABOLISM
- Volume
- 30
- Number
- 5
- Start Page
- 877
- End Page
- +
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/61927
- DOI
- 10.1016/j.cmet.2019.08.001
- ISSN
- 1550-4131
- Abstract
- 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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