Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration

Abstract

This article is available online at http://www.jlr.org identifi ed as essential fatty acids that must be consumed in the diet. Once consumed, however, LA and ALA can both be desaturated and elongated into more highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPA n-6), and docosahexaenoic (DHA) acids via the pathway shown in Fig. 1A . Delta-6 desaturase (D6D) performs the fi rst and rate-limiting step in this process, as well as the last step of desaturation for DHA and DPA n-6 synthesis. The D6D gene FADS2 was cloned in 1999 ( 2 ), and subsequently, a human case of D6D deficiency was identifi ed ( 3 ). The patient exhibited growth retardation accompanied by skin abnormalities, corneal ulceration, and feeding intolerance. Treatment with dietary AA and DHA restored normal growth and eliminated most other symptoms, underscoring the importance of the endogenous synthesis of these HUFAs.AA is a precursor to a host of signaling molecules known as eicosanoids, which include thromboxanes, leukotrienes, prostacyclins, and prostaglandins produced from the oxygenation of AA by cyclooxygenase and lipoxygenase enzymes. However, the symptoms of classic essential fatty acid defi ciency, growth retardation and dermatitis ( 1 ), are attributed to a loss of LA, not AA or eicosanoids. Because LA is an essential component of skin ceramides, LA defi ciency results in the disruption of the skin's water barrier function ( 4 ) and heat loss from skin ( 5 ). These side effects make investigation of AA defi ciency impossible by dietary manipulation without complications from LA defi ciency.DHA is found in large amounts in the retina, brain, and testes ( 6, 7 ). The role of DHA has been largely thought to be structural, increasing the fl uidity of cellular memAbstract Delta-6 desaturase (D6D) catalyzes the fi rst step in the synthesis of highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPAn-6), and docosahexaenoic (DHA) acids, as well as the last desaturation of DPAn-6 and DHA. We created D6D-null mice ( ؊ / ؊ ), which enabled us to study HUFA defi ciency without depleting their precursors. In ؊ / ؊ , no in vivo AA synthesis was detected after administration of [U-

A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1

“…Similarly, eicosanoid synthesis was restored by administration of arachidonic acid. Similar effects were observed in another fads2 Ϫ / Ϫ mouse by Stroud et al ( 5 ). These studies showed that the level and composition of HUFAs in the body highly depends on the conversion rate of the delta-6 desaturase, which is in turn regulated by supply with dietary fatty acids and hormone signaling.…”

“…By performing luciferase reporter gene assays, we showed that one of the two analyzed FADS2 promoter polyunderlined by previous reports of two different fads2 knockout mice ( 4,5 ). The assumption that there is a direct effect of FADS polymorphisms on the outcome of fatty acid-related diseases has been supported by Schaeffer et al ( 19 ), who reported an association of the FADS gene cluster with allergic rhinitis and atopic eczema, though without statistical signifi cance after correction for multiple testing.…”

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

“…For example, deletion of ⌬ 6 desaturase resulted in dermal and intestinal ulceration (38)(39)(40). In contrast, we report that ⌬ 5 desaturase null mice failed to thrive, gradually dying off at 5-6 weeks of age, with no survivors past 12 weeks of age ( Fig.…”

Genetic Variations in the Bovine Fatty Acid Desaturase 6 (FADS6) Are Associated with Fatty Acid Composition in Hanwoo Cattle

“…The FADS6 gene in humans is homologous to FADS2 (Stroud et al, 2009;Chen et al, 2015). FADS2 synthesizes Delta-6-desaturase (D6D) that catalyzes the first step in the synthesis of highly unsaturated fatty acid (HUFA) or LC-PUFA (Long chain-Poly unsaturated fatty acid (Stroud et al, 2009;Zheng et al, 2004). Therefore, it is necessary to investigate associations between genetic variants of FADS6 and FAC in muscle along with other genes involved in lipogenesis.…”

“…Functional study of bovine FADS6 has not been reported, but they were found to be highly similar to human FADS6. The FADS6 gene in humans is homologous to FADS2 (Stroud et al, 2009;Chen et al, 2015). FADS2 synthesizes Delta-6-desaturase (D6D) that catalyzes the first step in the synthesis of highly unsaturated fatty acid (HUFA) or LC-PUFA (Long chain-Poly unsaturated fatty acid (Stroud et al, 2009;Zheng et al, 2004).…”