title: Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis.
abstract: Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O(2)*- than those of lean littermates (P <.01). Ex vivo, all three SOD mimics decreased O(2)*- generation (P <.001) and totally inhibited lipid peroxidation (P <.001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P <.02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in humans.
authors.affiliation: Laboratoire d'Immunologie, UPRES 1833, Faculté et Hôpital Cochin, Université Paris V, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tran Van Nhieu
authors.forename: Didier
authors.initials: D
authors.lastname: Borderie
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Filomena
authors.initials: F
authors.lastname: Conti
authors.forename: Patrick
authors.initials: P
authors.lastname: Jaffray
authors.forename: Olivier
authors.initials: O
authors.lastname: Soubrane
authors.forename: Yvon
authors.initials: Y
authors.lastname: Calmus
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D013481:Superoxides; D009569:Nitric Oxide; D045304:Cytochromes c; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases