한빛사 논문
Won-Mook Choi1,2, Hee-Hoon Kim1, Myung-Ho Kim1, Resat Cinar3, Hyon-Seung Yi1,4, Hyuk Soo Eun1,4, Seok-Hwan Kim5, Young Jae Choi6, Young-Sun Lee1,7, So Yeon Kim1, Wonhyo Seo1,10, Jun-Hee Lee1, Young-Ri Shim1, Ye Eun Kim1, Keungmo Yang1, Tom Ryu1, Jung Hwan Hwang8, Chul-Ho Lee8, Hueng-Sik Choi9, Bin Gao10, Won Kim11, Sang Kyum Kim6, George Kunos3,*, Won-Il Jeong1,12,*
1 Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
2 Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
3 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
4 Department of Internal Medicine, Chungnam National University, School of Medicine, Daejeon 35015, Republic of Korea
5 Department of Surgery, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea
6 College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
7 Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea
8 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
9 School of the Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
10 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
11 Department of Internal Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
12 Lead Contact
*Corresponding author : George Kunos, Won-Il Jeong
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.
Keywords : alcoholic liver disease; metabotrophic glutamate receptor 5; 2-arachidonoylglycerol; cannabinoid receptor; Nrf2; transsulfuration pathway; xCT
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