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.
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.
Mol Med. 2014 Jan 17;20(1):1-9. doi: 10.2119/molmed.2013.00113.
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.
脂肪酸合酶（FASN）过度表达导致脂质代谢异常与炎症性肠病（IBD）的发展有关，该酶可催化长链脂肪酸的形成。C75 是一种合成的α-亚甲基-γ-丁内酯化合物，可抑制 FASN 活性。我们假设 C75 治疗可有效减轻实验性结肠炎的严重程度。雄性 C57BL/6 小鼠用 4%葡聚糖硫酸钠（DSS）喂养 7 天。从第 2 天到第 6 天，腹腔内给予 C75（5mg/kg 体重）或二甲基亚砜（DMSO）（载体）。每天监测临床参数。第 8 天处死小鼠进行组织学评估和结肠长度、趋化因子、细胞因子和炎症介质表达的测量。与载体组相比，C75 可将体重减轻率从 23%降低至 15%，从第 8 天开始。C75 治疗组的粪便出血、腹泻和结肠组织学损伤评分明显低于载体动物。C75 治疗后结肠缩短明显改善。C75 通过抑制半胱氨酸天冬氨酸蛋白酶-3 活性来保护结肠组织免受 DSS 诱导的凋亡。与载体组相比，C75 治疗组的巨噬细胞炎症蛋白 2、角质形成细胞衍生趋化因子、髓过氧化物酶活性和促炎细胞因子（肿瘤坏死因子-α、白细胞介素[IL]-1β和 IL-6）在结肠中的表达明显降低。与载体组相比，C75 治疗组在结肠炎小鼠中抑制了 FASN、环氧化酶-2 和诱导型一氧化氮合酶表达以及结肠组织中 IκB 降解的升高。C75 给药减轻了结肠损伤的严重程度，并抑制了 DSS 诱导的结肠炎中炎症途径的激活。因此，抑制 FASN 可能代表治疗 IBD 的一种有吸引力的治疗潜力。
