Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model
Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model
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DOI：
10.1194/jlr.m024216
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发表时间：
2012-07-01
影响因子：
6.5
通讯作者：
Chapkin, Robert S.
中科院分区：
文献类型：
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作者：
Fan, Yang-Yi;Monk, Jennifer M.;Chapkin, Robert S.
花生四烯酸 (20:4(Delta 5,8,11,14), AA) 衍生的类二十烷酸可调节炎症并促进癌症发展。先前的研究以前列腺素酶为目标，试图调节 AA 代谢。然而，由于围绕使用旨在靶向 Ptgs2（环氧合酶 2）及其下游靶点的药剂的安全性问题，确定 Ptgs2 上游的新靶点非常重要。因此，我们确定了拮抗组织 AA 水平作为抑制 AA 衍生类二十烷酸的新方法的效用。 Fads1（Delta 5 去饱和酶）基因的系统性破坏会相互改变小鼠组织中二高-γ-亚麻酸（20:3（Delta 8,11,14），DGLA）和 AA 的水平，导致 1 系列衍生的前列腺素显着增加，同时 2 系列衍生的前列腺素减少。缺乏 AA 衍生的类二十烷酸，例如。例如，PGE(2) 与肠隐窝增殖紊乱、免疫细胞稳态以及对急性炎症挑战的敏感性升高有关。此外，无效小鼠未能茁壮成长，在 12 周龄时死亡。膳食补充 AA 可将无效小鼠的寿命延长至与野生型小鼠相当的水平。(Jlr) 我们认为，这种新的小鼠模型将扩大我们对 AA 及其代谢物如何介导炎症和促进恶性转化的理解，最终目标是确定 Ptgs2 上游的新药物靶点。-Fan、Y-Y.、J. M. Monk、T. Y. Hou、E. Callway、L. Vincent、B. Weeks、P. Yang 和R.S.查普金。花生四烯酸缺陷（Fads1 敲除）小鼠模型的表征。 J.脂质研究。 2012。53：1287-1295。
Arachidonic acid (20:4(Delta 5,8,11,14), 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 (Delta 5 desaturase) gene reciprocally altered the levels of dihomo-gamma-linolenic acid (20:3(Delta 8,11,14), 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., PGE(2), 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.(Jlr) 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.-Fan, Y-Y., J. M. Monk, T. Y. Hou, E. Callway, L. Vincent, B. Weeks, P. Yang, and R. S. Chapkin. Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model. J. Lipid Res. 2012. 53: 1287-1295.