title: Transient receptor potential vanilloid 1 gene deficiency ameliorates hepatic injury in a mouse model of chronic binge alcohol-induced alcoholic liver disease.
abstract: Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy-octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca(2+) levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-α, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol-mediated induction of plasminogen activator inhibitor-1, an important alcohol-induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; College of Food Science and Engineering, Jilin Agricultural University, Changchun, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.
authors.forename: Juliane I
authors.initials: JI
authors.lastname: Beier
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Ramsden
authors.affiliation: Department of Pediatrics, University of California San Diego, San Diego, California.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; Division of Gastroenterology, Department of Medicine, Robley Rex Veterans Medical Center, Louisville, Kentucky.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky. Electronic address: i0kirp01@louisville.edu.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Kirpich
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D054426:Chemokine CXCL2 / Q000097:blood; D004195:Disease Models, Animal; D000431:Ethanol / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood; D008024:Ligands; D019787:Linoleic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000235:genetics* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D015850:Interleukin-6; D008024:Ligands; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D000431:Ethanol; D019787:Linoleic Acid; C505409:Casp3 protein, mouse; D053148:Caspase 3