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 longchain 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.

IL-22 exacerbates weight loss in a murine model of chronic pulmonary Pseudomonas aeruginosa infection

“…Despite its reported protective role against a range of pulmonary pathogens [8], [9], [10], [11], [12], we found no evidence that IL-22 is critical in preventing the establishment of chronic pulmonary P. aeruginosa infection. The most striking effect of IL-22 was in relation to infection-associated weight loss.…”

“…In respiratory infections, IL-22 provides critical immunity against Klebsiella pneumoniae [8], Streptococcus pneumoniae [9], Chlamydia muridarum [10], influenza [11], [12], as well as the CF pathogen Aspergillus fumigatus [13]. A protective role of IL-22 against pulmonary P. aeruginosa infection potentially exists [14], [15], but is yet to be clearly defined.…”

Fatty acid synthase regulates the pathogenicity of Th17 cells

“…Previous studies have shown inhibition or deletion of ACC1 reduces Th17 cell generation and skews differentiation toward T regs [7,8]. Inhibition of FASN was also shown to lessen DSSinduced colitis severity in mice [25]. The influence of FAS on Th17 pathogenicity downstream of ACC1, however, is unknown.…”

Rosmarinus officinalis L. extract ameliorates intestinal inflammation through MAPKs/NF-κB signaling in a murine model of acute experimental colitis

“…1 It is characterized by ulceration, bleeding of the colonic mucosa with an imbalance in the intestinal mucosal immune system which shifts toward the pro-inflammatory side. 3 Increase in pro-inflammatory cytokines production, infiltration of inflammatory cells, nitric oxide production derived from inducible nitric oxide synthase (iNOS), activation of NF-κB and MAPKs signaling in colonic tissue are apparently associated with the pathogenesis of ulcerative colitis. 3 Increase in pro-inflammatory cytokines production, infiltration of inflammatory cells, nitric oxide production derived from inducible nitric oxide synthase (iNOS), activation of NF-κB and MAPKs signaling in colonic tissue are apparently associated with the pathogenesis of ulcerative colitis.…”

“…3 Increase in pro-inflammatory cytokines production, infiltration of inflammatory cells, nitric oxide production derived from inducible nitric oxide synthase (iNOS), activation of NF-κB and MAPKs signaling in colonic tissue are apparently associated with the pathogenesis of ulcerative colitis. 3 Thus, suppressing the inflammatory pathways will be a reasonable strategy to alleviate IBD including ulcerative colitis. 3 Thus, suppressing the inflammatory pathways will be a reasonable strategy to alleviate IBD including ulcerative colitis.…”