Fads2ノックアウトマウスによるアラキドン酸とドコサヘキサエン酸の新機能の発見

Abstract

In mammals, arachidonic acid (ARA) and docosahexaenoic acid (DHA) play important physiological roles as precursors of eicosanoids and docosanoids, respectively. However, a full scope of the function of these fatty acids is yet to be elucidated. A major obstacle is endogenous synthesis of ARA and DHA from precursors. It is not possible to create ARA deficiency by dietary manipulation without depleting linoleic acid, which is an essential component of skin ceramides. Also, DHA deficiency cannot be created without a compensatory increase in 22:5 n-6. To overcome these obstacles, mice lacking the Fads2 gene that encodes the first step of ARA and DHA synthesis were created. When Fads2-null mice were fed a diet lacking ARA and DHA but containing sufficient linoleic and alpha-linolenic acid, they exhibited previously undocumented phenotypes. The Fads2-null mice developed ulcerative dermatitis after 4 months of age, which was distinct from dry, scaly dermatitis observed in classic linoleic acid deficiency. Fads2-null males exhibited complete arrest of sperm development at the stage of acrosome biogenesis. Intestinal ulcer was observed at duodenum and the ileo-cecal junction. In liver, lipid droplets were primarily localized in a periportal area. Dietary ARA prevented dermatitis and intestinal ulcer, whereas dietary DHA was ineffective. The male fertility and sperm formation were fully recovered by dietary DHA, whereas ARA was only partially effective. Either ARA or DHA supplementation prevented fatty liver. Although some of these phenotypes are likely due to reduced eicosanoid formation, the exact mechanism is yet to be elucidated.