title: Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes.
abstract: Chronic alcohol consumption results in hepatotoxicity, steatosis, hypoxia, increased expression of inducible nitric oxide synthase (iNOS) and decreased activities of mitochondrial respiratory enzymes. The impact of these changes on cellular respiration and their interaction in a cellular setting is not well understood. In the present study we tested the hypothesis that nitric oxide (NO)-dependent modulation of cellular respiration and the sensitivity to hypoxic stress is increased following chronic alcohol consumption. This is important since NO has been shown to regulate mitochondrial function through its interaction with cytochrome c oxidase, although at higher concentrations, and in combination with reactive oxygen species, can result in mitochondrial dysfunction. We found that hepatocytes isolated from alcohol-fed rats had decreased mitochondrial bioenergetic reserve capacity and were more sensitive to NO-dependent inhibition of respiration under room air and hypoxic conditions. We reasoned that this would result in greater hypoxic stress in vivo, and to test this, wild-type and iNOS(-/-) mice were administered alcohol-containing diets. Chronic alcohol consumption resulted in liver hypoxia in the wild-type mice and increased levels of hypoxia-inducible factor 1 α in the peri-venular region of the liver lobule. These effects were attenuated in the alcohol-fed iNOS(-/-) mice suggesting that increased mitochondrial sensitivity to NO and reactive nitrogen species in hepatocytes and iNOS plays a critical role in determining the response to hypoxic stress in vivo. These data support the concept that the combined effects of NO and ethanol contribute to an increased susceptibility to hypoxia and the deleterious effects of alcohol consumption on liver.
authors.affiliation: Center for Free Radical Biology, University of Alabama at Birmingham, AL 35294, USA.
authors.forename: Blake R
authors.initials: BR
authors.lastname: Zelickson
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Benavides
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Balu K
authors.initials: BK
authors.lastname: Chacko
authors.forename: Aparna
authors.initials: A
authors.lastname: Venkatraman
authors.forename: Aimee
authors.initials: A
authors.lastname: Landar
authors.forename: Angela M
authors.initials: AM
authors.lastname: Betancourt
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Bailey
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D004032:Diet; D004734:Energy Metabolism / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009569:Nitric Oxide; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II