Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model[S]

  1. Robert S. Chapkin1,*,†§
  1. *Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843
  2. †Center for Environmental and Rural Health, Texas A&M University, College Station, TX 77843
  3. §Departments of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843
  4. ††Veterinary Pathobiology, Texas A&M University, College Station, TX 77843
  5. §§Department of Cancer Biology University of Texas MD Anderson Cancer Center, Houston, TX 77030

    Abstract

    Arachidonic acid (20:4Δ5,8,11,14, AA)-derived eicosanoids regulate inflammation and promote cancer development. Previous studies have targeted prostaglandin enzymes in an attempt to modulate AA metabolism. However, due to safety concerns surrounding the use of pharmaceutical agents designed to target Ptgs2 (cyclooxygenase 2) and its downstream targets, it is important to identify new targets upstream of Ptgs2. Therefore, we determined the utility of antagonizing tissue AA levels as a novel approach to suppressing AA-derived eicosanoids. Systemic disruption of the Fads1 (Δ5 desaturase) gene reciprocally altered the levels of dihomo-γ-linolenic acid (20:3Δ8,11,14, DGLA) and AA in mouse tissues, resulting in a profound increase in 1-series-derived and a concurrent decrease in 2-series-derived prostaglandins. The lack of AA-derived eicosanoids, e.g., PGE2, was associated with perturbed intestinal crypt proliferation, immune cell homeostasis, and a heightened sensitivity to acute inflammatory challenge. In addition, null mice failed to thrive, dying off by 12 weeks of age. Dietary supplementation with AA extended the longevity of null mice to levels comparable to wild-type mice. We propose that this new mouse model will expand our understanding of how AA and its metabolites mediate inflammation and promote malignant transformation, with the eventual goal of identifying new drug targets upstream of Ptgs2.

    Footnotes

    • ↵1 To whom correspondence should be addressed. e-mail: r-chapkin{at}tamu.edu

    • Abbreviations:
      AA
      arachidonic acid
      Ptgs2
      cyclooxygenase 2
      DGLA
      dihomo-γ-linolenic acid
      DSS
      dextran sodium sulphate
      EdU
      5-ethynyl-2´-deoxyuridine
      Fads1
      fatty acid desaturase 1 (Δ5 desaturase)
      Het
      heterozygous
      IL
      interleukin
      LA
      linoleic acid
      MHC II
      major histocompatibility complex class II
      PGE
      prostaglandin E
      PI(4,5)P2
      phosphatidylinositol-4,5-bisphosphate
      TNFα
      tumor necrosis factor α
      Wt
      wild-type

    • This work was supported by Cancer Prevention and Research Institute of Texas (CPRIT) Grant RP120028. J. M. Monk is recipient of a Natural Sciences and Engineering Research Council of Canada postdoctoral fellowship (PDF-388466-2010). T. Y. Hou is recipient of a Natural Sciences and Engineering Research Council of Canada predoctoral fellowship (PGSD2-403986-2011). Mutant Fads1 mice were generated in collaboration with the Texas Institute for Genomic Medicine (TIGM).

    • ↵[S] The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four figures and five tables.

    • Received January 4, 2012.
    • Revision received March 19, 2012.
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    1. First Published on April 25, 2012, doi: 10.1194/jlr.M024216 The Journal of Lipid Research, 53, 1287-1295.
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