Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis.

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.

• Authors: Won-Mook Choi, Hee-Hoon Kim, Myung-Ho Kim, Resat Cinar, Hyon-Seung Yi, Hyuk Soo Eun, Seok-Hwan Kim, Young Jae Choi, Young-Sun Lee, So Yeon Kim, Wonhyo Seo, Jun-Hee Lee, Young-Ri Shim, Ye Eun Kim, Keungmo Yang, Tom Ryu, Jung Hwan Hwang, Chul-Ho Lee, Hueng-Sik Choi, Bin Gao, Won Kim, Sang Kyum Kim, George Kunos, Won-Il Jeong
• Journal: Cell metabolism (Cell Metab) Vol. 30 Issue 5 Pg. 877-889.e7 (11 05 2019) ISSN: 1932-7420 [Electronic] United States
• PMID: 31474565 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Amino Acid Transport System y+
• Arachidonic Acids
• CNR1 protein, human
• CNR1 protein, mouse
• Endocannabinoids
• GRM5 protein, human
• Glycerides
• Grm5 protein, mouse
• Receptor, Cannabinoid, CB1
• Receptor, Metabotropic Glutamate 5
• SLC7A11 protein, human
• Slc7a11 protein, mouse
• Glutamic Acid
• glyceryl 2-arachidonate

Topics

• Adult
• Aged
• Amino Acid Transport System y+ (antagonists & inhibitors, genetics, metabolism)
• Animals
• Arachidonic Acids (metabolism)
• Endocannabinoids (metabolism)
• Fatty Liver, Alcoholic (blood, pathology)
• Female
• Glutamic Acid (metabolism)
• Glycerides (metabolism)
• HEK293 Cells
• Hep G2 Cells
• Hepatic Stellate Cells (metabolism)
• Hepatocytes (metabolism)
• Humans
• Lipogenesis (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Receptor, Cannabinoid, CB1 (metabolism)
• Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (genetics)
• Transfection