Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis

Cell Metab. 2019 Nov 5;30(5):877-889.e7. doi: 10.1016/j.cmet.2019.08.001. Epub 2019 Aug 29.


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: 2-arachidonoylglycerol; Nrf2; alcoholic liver disease; cannabinoid receptor; metabotrophic glutamate receptor 5; transsulfuration pathway; xCT.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Aged
  • Amino Acid Transport System y+ / antagonists & inhibitors
  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Arachidonic Acids / metabolism
  • Endocannabinoids / metabolism
  • Fatty Liver, Alcoholic / blood*
  • Fatty Liver, Alcoholic / 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
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Signal Transduction / genetics*
  • Transfection


  • 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