title: TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity.
abstract: NAFLD is a clinically progressive disease with steatosis, inflammation, endothelial dysfunction and fibrosis being the stages where clinical intervention becomes necessary. Lack of early biomarkers and absence of a FDA approved drug obstructs efforts for effective treatment. NAFLD progression is strongly linked to a balance between liver injury, tissue regeneration and the functioning of endogenous defense mechanisms. The failure of the defense pathways to resist the tissue damage arising from redox stress, one of the "multiple hits" in disease progression, give rise to heightened inflammation and occasional fibrosis. We introduce an endogenous defense mechanism in the liver that is mediated by TRPV4, a transient receptor potential calcium-permeable ion channel that responds to the cytotoxic liver environment and negatively regulates CYP2E1, a cytochrome p450 enzyme. Using Trpv4-/- mice and cultured primary cells, we show that TRPV4 is activated both by damage associated molecular pattern HMGB1 and collagen in diseased Kupffer cells that in turn activate the endothelial NOS (NOS3) to release nitric oxide (NO). The diffusible NO acts in a paracrine fashion in neighboring hepatocytes to deactivate the redox toxicity induced by CYP2E1. We also find that CYP2E1-mediated TRPV4 repression in late stages causes an unrestricted progression of disease. Thus, TRPV4 functions as a sensor of cell stress in the diseased fatty liver and constitutes an endogenous defense molecule, a novel concept with potential for therapeutic approaches against NAFLD, perhaps also against hepatic drug toxicity in general.
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Ratanesh K
authors.initials: RK
authors.lastname: Seth
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Suvarthi
authors.initials: S
authors.lastname: Das
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Diptadip
authors.initials: D
authors.lastname: Dattaroy
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Chandrashekaran
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Firas
authors.initials: F
authors.lastname: Alhasson
authors.affiliation: Metabolon Inc. Research Triangle Park, NC 27713, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Michelotti
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Nagarkatti
authors.affiliation: Division of Gastroenterology, Duke University, Durham, NC 27707, USA.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, AL 35294, USA.
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
authors.affiliation: Department of Neurology, Duke University School of Medicine, Durham, NC 27707, USA. Electronic address: liedt001@duke.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA. Electronic address: schatt@mailbox.sc.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D009569:Nitric Oxide; D019392:Cytochrome P-450 CYP2E1; D052250:Nitric Oxide Synthase Type III
keywords: Cation channel mechanosensor; Hydroxynonenal; Lipid peroxidation; Liver; Oxidative stress