Molecular Medicine

, Volume 20, Issue 1, pp 1–9 | Cite as

Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

  • Shingo Matsuo
  • Weng-Lang Yang
  • Monowar Aziz
  • Shingo Kameoka
  • Ping Wang
Research Article


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.



We thank Lana M Corbo for editorial assistance. This study was supported in part by National Institutes of Health grants GM057468, GM053008 and HL076179 (to P Wang).


  1. 1.
    Xavier RJ, Podolsky DK. (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature. 448:427–34.CrossRefGoogle Scholar
  2. 2.
    Inflammatory bowel disease (IBD). Atlanta (GA): Centers for Disease Control and Prevention; [updated 2011 Jul 15; cited 2013 Dec 23]. Available from:
  3. 3.
    Sonnenberg A. (1989) Disability from inflammatory bowel disease among employees in West Germany. Gut. 30:367–70.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Isaacs KL, Sartor RB, Haskill S. (1992) Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology. 103:1587–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Harris ML, et al. (1992) Free radicals and other reactive oxygen metabolites in inflammatory bowel disease: cause, consequence or epiphenomenon? Pharmacol. Ther. 53:375–408.CrossRefPubMedGoogle Scholar
  6. 6.
    Reilly PM, Schiller HJ, Bulkley GB. (1991) Pharmacologic approach to tissue injury mediated by free radicals and other reactive oxygen metabolites. Am. J. Surg. 161:488–503.CrossRefPubMedGoogle Scholar
  7. 7.
    Simopoulos AP. (1991) Omega-3 fatty acids in health and disease and in growth and development. Am. J. Clin. Nutr. 54:438–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Unger RH. (2003) The physiology of cellular liporegulation. Annu. Rev. Physiol. 65:333–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Savary S, et al. (2012) Fatty acids: induced lipotoxicity and inflammation. Curr. Drug Metab. 13:1358–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Toborek M, Lee YW, Garrido R, Kaiser S, Hennig B. (2002) Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells. Am. J. Clin. Nutr. 75:119–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Martins de Lima T, et al. (2007) Mechanisms by which fatty acids regulate leucocyte function. Clin. Sci. (Lond). 113:65–77.CrossRefGoogle Scholar
  12. 12.
    Huang S, et al. (2012) Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J. Lipid Res. 53:2002–13.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chirala SS, Wakil SJ. (2004) Structure and function of animal fatty acid synthase. Lipids. 39:1045–53.CrossRefPubMedGoogle Scholar
  14. 14.
    Consolazio A, et al. (2006) Overexpression of fatty acid synthase in ulcerative colitis. Am. J. Clin. Pathol. 126:113–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Kuhajda FP, et al. (2000) Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc. Natl. Acad. Sci. U. S. A. 97:3450–4.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Flavin R, Peluso S, Nguyen PL, Loda M. (2010) Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 6:551–62.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Menendez JA, Lupu R. (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer. 7:763–77.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim EK, et al. (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J. Biol. Chem. 279:19970–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim TW, et al. (2006) Involvement of lymphocytes in dextran sulfate sodium-induced experimental colitis. World J. Gastroenterol. 12:302–5.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Krieglstein CF, et al. (2001) Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide. J. Exp. Med. 194:1207–18.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ohkawara T, et al. (2011) DNA vaccination targeting macrophage migration inhibitory factor prevents murine experimental colitis. Clin. Exp. Immunol. 163:113–22.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Elmore S. (2007) Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35:495–516.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Chin AC, Parkos CA. (2006) Neutrophil transepithelial migration and epithelial barrier function in IBD: potential targets for inhibiting neutrophil trafficking. Ann. N. Y. Acad. Sci. 1072:276–87.CrossRefPubMedGoogle Scholar
  24. 24.
    Dutra RC, et al. (2011) Preventive and therapeutic euphol treatment attenuates experimental colitis in mice. PLoS One. 6: e27122.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Alex P, et al. (2009) Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm. Bowel Dis. 15:341–52.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A. (2006) Biomarkers of oxidative damage in human disease. Clin. Chem. 52:601–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Karrasch T, Jobin C. (2008) NF-kappaB and the intestine: friend or foe? Inflamm. Bowel Dis. 14:114–24.CrossRefPubMedGoogle Scholar
  28. 28.
    Lawrence T. (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb. Perspect. Biol. 1: a001651.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lawrence T, Bebien M, Liu GY, Nizet V, Karin M. (2005) IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature. 434:1138–43.CrossRefPubMedGoogle Scholar
  30. 30.
    Dudhgaonkar SP, Tandan SK, Kumar D, Raviprakash V, Kataria M. (2007) Influence of simultaneous inhibition of cyclooxygenase-2 and inducible nitric oxide synthase in experimental colitis in rats. Inflammopharmacology. 15:188–95.CrossRefPubMedGoogle Scholar
  31. 31.
    Karvellas CJ, Fedorak RN, Hanson J, Wong CK. (2007) Increased risk of colorectal cancer in ulcerative colitis patients diagnosed after 40 years of age. Can. J. Gastroenterol. 21:443–6.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Girardin M, et al. (2012) First-line therapies in inflammatory bowel disease. Digestion. 86 (Suppl. 1):6–10.CrossRefPubMedGoogle Scholar
  33. 33.
    Shores DR, Binion DG, Freeman BA, Baker PR. (2011) New insights into the role of fatty acids in the pathogenesis and resolution of inflammatory bowel disease. Inflamm. Bowel Dis. 17:2192–204.CrossRefPubMedGoogle Scholar
  34. 34.
    Rashid A, et al. (1997) Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am. J. Pathol. 150:201–8.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Heimerl S, et al. (2006) Alterations in intestinal fatty acid metabolism in inflammatory bowel disease. Biochim. Biophys. Acta. 1762:341–50.CrossRefPubMedGoogle Scholar
  36. 36.
    Wei X, et al. (2012) Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2. Cell Host Microbe. 11:140–52.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cooper HS, Murthy SN, Shah RS, Sedergran DJ. (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 69:238–49.PubMedGoogle Scholar
  38. 38.
    Martinez JA, et al. (2006) Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis. Gastroenterology, 131:579–88.CrossRefPubMedGoogle Scholar
  39. 39.
    Iwamoto M, Koji T, Makiyama K, Kobayashi N, Nakane PK. (1996) Apoptosis of crypt epithelial cells in ulcerative colitis. J. Pathol. 180:152–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Maloy KJ, Powrie F. (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 474:298–306.CrossRefGoogle Scholar
  41. 41.
    De Filippo K, Henderson RB, Laschinger M, Hogg N. (2008) Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways. J. Immunol. 180:4308–15.CrossRefPubMedGoogle Scholar
  42. 42.
    Haziot A, Hijiya N, Gangloff SC, Silver J, Goyert SM. (2001) Induction of a novel mechanism of accelerated bacterial clearance by lipopolysaccharide in CD14-deficient and Toll-like receptor 4-deficient mice. J. Immunol. 166:1075–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Lee WL, Downey GP. (2001) Neutrophil activation and acute lung injury. Curr. Opin. Crit. Care. 7:1–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Abraham E. (2003) Neutrophils and acute lung injury. Crit. Care Med. 31:S195–9.CrossRefGoogle Scholar
  45. 45.
    Farooq SM, et al. (2009) Therapeutic effect of blocking CXCR2 on neutrophil recruitment and dextran sodium sulfate-induced colitis. J. Pharmacol. Exp. Ther. 329:123–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Nathan CF. (1987) Secretory products of macrophages. J. Clin. Invest. 79:319–26.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Del Rio D, Stewart AJ, Pellegrini N. (2005) A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr. Metab. Cardiovasc. Dis. 15:316–28.CrossRefPubMedGoogle Scholar
  48. 48.
    Koppula S, Kumar H, Kim IS, Choi DK. (2012) Reactive oxygen species and inhibitors of inflammatory enzymes, NADPH oxidase, and iNOS in experimental models of Parkinson’s disease. Mediators Inflamm. 2012: 823902.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Vane JR, et al. (1994) Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Natl. Acad. Sci. U. S. A. 91:2046–50.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Loftus TM, et al. (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 288:2379–81.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Shingo Matsuo
    • 1
    • 2
  • Weng-Lang Yang
    • 1
  • Monowar Aziz
    • 1
  • Shingo Kameoka
    • 2
  • Ping Wang
    • 1
  1. 1.Department of SurgeryHofstra North Shore-Long Island Jewish School of Medicine, and The Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of Surgery IITokyo Women’s Medical UniversityTokyoJapan

Personalised recommendations