title: Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model.
abstract: Arachidonic acid (20:4(Δ5,8,11,14), 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 (20:3(Δ8,11,14), 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.
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Yang-Yi
authors.initials: YY
authors.lastname: Fan
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Monk
authors.forename: Tim Y
authors.initials: TY
authors.lastname: Hou
authors.forename: Evelyn
authors.initials: E
authors.lastname: Callway
authors.forename: Logan
authors.initials: L
authors.lastname: Vincent
authors.forename: Brad
authors.initials: B
authors.lastname: Weeks
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage; D000090943:Delta-5 Fatty Acid Desaturase; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000172:deficiency / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D015777:Eicosanoids; D016718:Arachidonic Acid; D044943:Fatty Acid Desaturases