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Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model
Yang-Yi Fan1, Jennifer M Monk, Tim Y Hou
1Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA.
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.
Insights
Targeting arachidonic acid (AA) metabolism upstream of Ptgs2 is a novel strategy. Disrupting Fads1 in mice altered eicosanoid production, impacting inflammation and survival, highlighting AA
Area of Science:
- Biochemistry
- Immunology
- Cancer Biology
Background:
- Arachidonic acid (AA)-derived eicosanoids are key regulators of inflammation and cancer.
- Current therapeutic strategies targeting downstream prostaglandin enzymes (e.g., Ptgs2) face safety concerns.
- Identifying upstream targets in AA metabolism is crucial for developing safer interventions.
Purpose of the Study:
- To investigate the therapeutic potential of antagonizing tissue AA levels as a novel approach.
- To understand the role of upstream regulators in AA metabolism and its downstream effects.
- To establish a new mouse model for studying AA-mediated inflammation and cancer development.
Main Methods:
- Systemic disruption of the Fads1 (Δ5 desaturase) gene in mice.
- Analysis of tissue levels of dihomo-γ-linolenic acid (DGLA) and AA.
- Assessment of prostaglandin production (1-series vs. 2-series).
- Evaluation of intestinal crypt proliferation, immune cell homeostasis, and inflammatory response.
- Dietary supplementation with AA to assess its impact on survival.
Main Results:
- Fads1 gene disruption led to reciprocal changes in DGLA and AA levels.
- A significant increase in 1-series prostaglandins and decrease in 2-series prostaglandins was observed.
- Lack of AA-derived eicosanoids resulted in impaired intestinal crypt proliferation, altered immune cell homeostasis, and increased susceptibility to inflammation.
- Fads1 null mice exhibited poor thriving and premature death, which was rescued by dietary AA supplementation.
Conclusions:
- Antagonizing tissue AA levels via Fads1 disruption offers a novel strategy to suppress AA-derived eicosanoids.
- This approach impacts critical physiological processes, including inflammation and cell proliferation.
- The Fads1 knockout mouse model provides a valuable tool for exploring AA metabolism in disease and identifying new therapeutic targets upstream of Ptgs2.
