title: The role of iNOS in cholesterol-induced liver fibrosis.
abstract: Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1α stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Anavi
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Eisenberg-Bord
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hahn-Obercyger
authors.affiliation: Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Genin
authors.affiliation: Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Pines
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D059305:Diet, High-Fat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D051381:Rats
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002784:Cholesterol; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse