title: Fatty acid synthase inhibitor C75 ameliorates experimental colitis.
abstract: Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or dimethyl sulfoxide (DMSO) (vehicle) was administered intraperitoneally from d 2 to 6. Clinical parameters were monitored daily. Mice were euthanized on d 8 for histological evaluation and measurements of colon length, chemokine, cytokine and inflammatory mediator expression. C75 significantly reduced body weight loss from 23% to 15% on d 8, compared with the vehicle group. The fecal bleeding, diarrhea and colon histological damage scores in the C75-treated group were significantly lower than scores in the vehicle animals. Colon shortening was significantly improved after C75 treatment. C75 protected colon tissues from DSS-induced apoptosis by inhibiting caspase-3 activity. Macrophage inflammatory protein 2, keratinocyte-derived chemokine, myeloperoxidase activity and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β and IL-6) in the colon were significantly downregulated in the C75-treated group, compared with the vehicle group. Treatment with C75 in colitis mice inhibited the elevation of FASN, cyclooxygenase-2 and inducible nitric oxide synthase expression as well as IκB degradation in colon tissues. C75 administration alleviates the severity of colon damage and inhibits the activation of inflammatory pathways in DSS-induced colitis. Thus, inhibition of FASN may represent an attractive therapeutic potential for treating IBD.
authors.affiliation: Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, and The Feinstein Institute for Medical Research, Manhasset, New York, United States of America Department of Surgery II, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, and The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Weng-Lang
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, and The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Monowar
authors.initials: M
authors.lastname: Aziz
authors.affiliation: Department of Surgery II, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kameoka
authors.affiliation: Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, and The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D018925:Chemokines; D016207:Cytokines; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone