New insights into the role of fatty acids in the pathogenesis and resolution of inflammatory bowel disease

Shores, Darla R.; Binion, David G.; Freeman, Bruce Α.; Baker, Paul R. S.

doi:10.1002/ibd.21560

Cited by 72 publications

(67 citation statements)

References 128 publications

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“…Thus, there is still an unmet medical need for the innovated approaches for treating IBD patients. In this study, we demonstrate the therapeutic potential of C75, a FASN inhibitor, against a murine model of DSSinduced colitis in terms of attenuating The abnormalities in FA metabolism have been reported in IBD, which can be considered as one of the etiologies for the development of this disease (33). We have demonstrated that FASN expression extends from the top of the crypt in the sham mice to the entire mucosa in the colitis mice, detected by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 55%

Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

Matsuo¹,

Yang

Aziz

et al. 2013

Mol Med

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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.

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Section: Discussionmentioning

confidence: 55%

Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

Matsuo¹,

Yang

Aziz

et al. 2013

Mol Med

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“…This study is the first to our knowledge to show a link between PPARg and TFF3. Some fatty acids can promote inflammation, whereas others like CLA can be protective in animal models of IBD (17,(27)(28)(29)(30)(31). This fatty acid has positive health effects in animal models of inflammatory disorders such as atherosclerosis, diabetes, and IBD [reviewed in (32,33)].…”

Section: Discussionmentioning

confidence: 99%

Dietary Conjugated Linoleic Acid Activates PPARγ and the Intestinal Trefoil Factor in SW480 Cells and Mice with Dextran Sulfate Sodium-Induced Colitis3

Borniquel

Jädert

Lundberg

2012

The Journal of Nutrition

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A central event in inflammatory bowel disease is the disruption of the mucosal homeostasis. Trefoil peptides [(TFF)] are emerging as key mediators in the defense and repair of the gastrointestinal mucosa. Here, we demonstrate induction of TFF by CLA with therapeutic antiinflammatory effects in a mouse model of inflammatory bowel disease. SW480 cells were treated with linoleic acid or CLA (0-2.5 μmol/L) in the absence or presence of the PPARγ inhibitor GW9662. Cells treated with CLA showed an upregulation of the intestinal trefoil factor, which was prevented by pretreatment with GW9662. Dextran sulfate sodium (2%) was used to induce colitis in mice and they were simultaneously fed with a standard or a CLA-supplemented (100 mg · kg(-1) · d(-1)) diet for 7 d. The CLA-enriched diet prevented the colon shortening induced by DSS and markedly reduced the disease activity index and the colonic expression of inducible NO synthase and NF-κB. Immunohistochemistry revealed an increase in PPARγ and TFF3 expression after CLA administration. Altogether, these results indicate that dietary CLA protects against DSS-induced colitis in a process involving induction of PPARγ and TFF3.

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“…Several mechanisms may explain how long-chain n-3 PUFAs may influence risk of UC 9 51. First, long-chain n-3 PUFAs acting as a competitive substrate decreases the production of the eicosanoids from arachidonic acid, and reduces membrane levels of leukotriene B4.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, long-chain n-3 PUFAs affect cell membrane structure and inhibit dimerisation and activation of the toll-like receptor 4, which is important in mediating intestinal inflammation 52. In mouse models, administration of n-3 PUFA before induction of colitis appears to protect against the development of colitis 51. Second, dietary long-chain n-3 PUFAs inhibit vascular adhesion molecule expression in contrast to arachidonic acid which increases intercellular adhesion molecule 1 expression 9.…”

Section: Discussionmentioning

confidence: 99%

“…Second, dietary long-chain n-3 PUFAs inhibit vascular adhesion molecule expression in contrast to arachidonic acid which increases intercellular adhesion molecule 1 expression 9. Third, long-chain n-3 PUFAs also modulate the adaptive immune response by inhibiting T-cell proliferation and antigen presentation and binding to nuclear receptors which function as lipid sensors regulating PPARγ-mediated NFκB activation 9 51…”

Section: Discussionmentioning

confidence: 99%

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Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease

Ananthakrishnan

Khalili

Konijeti

et al. 2013

Gut

419

276

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Introduction Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohn’s disease (CD) and ulcerative colitis (UC) are limited and conflicting. Methods We conducted a prospective study of women enrolled in the Nurses’ Health Study cohorts. Diet was prospectively ascertained every four years using a validated semi-quantitative food frequency questionnaire. Self-reported CD and UC were confirmed through medical record review. We examined the effect of energy-adjusted cumulative average total fat intake as well as specific types of fat and fatty acids on the risk of CD and UC using Cox proportional hazards models adjusting for potential confounders. Results Among 170,805 women, we confirmed 269 incident cases of CD (incidence 8/100,000 person-years) and 338 incident cases of UC (incidence 10/100,000 person-years) over 26 years and 3,317,338 person-years of follow-up. Cumulative energy-adjusted intake of total fat, saturated fats, unsaturated fats, n-6 and n-3 polyunsaturated fatty acids (PUFA) were not associated with risk of CD or UC. However, greater intake of long-chain n-3 PUFA was associated with a trend towards lower risk of UC (Hazard ratio (HR) 0.72, 95% CI 0.51 – 1.01). In contrast, high long-term intake of trans-unsaturated fatty acids was associated with a trend towards an increased incidence of UC (HR 1.34, 95% CI 0.94 – 1.92). Conclusion A high intake of dietary long-chain n-3 PUFA may be associated with a reduced risk of UC. In contrast, high intake of trans-unsaturated fats may be associated with an increased risk of UC.

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New insights into the role of fatty acids in the pathogenesis and resolution of inflammatory bowel disease

Cited by 72 publications

References 128 publications

Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

Dietary Conjugated Linoleic Acid Activates PPARγ and the Intestinal Trefoil Factor in SW480 Cells and Mice with Dextran Sulfate Sodium-Induced Colitis3

Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease

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