Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration.
Delta-6 desaturase (D6D) catalyzes the first 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 deficiency without depleting their precursors. In -/-, no in vivo AA synthesis was detected after administration of [U-(13)C]linoleic acid (LA), indicating absence of D6D isozyme. Unexpectedly, all of the -/- developed ulcerative dermatitis when fed a purified diet lacking D6D products but containing ample LA. The -/- also exhibited splenomegaly and ulceration in duodenum and ileocecal junction. Male -/- lacked normal spermatozoa with a severe impairment of spermiogenesis. Tissue HUFAs in -/- declined differentially: liver AA and DHA by 95%, and a smaller decrease in brain and testes. Dietary AA completely prevented dermatitis and intestinal ulcers in -/-. DPAn-6 was absent in -/- brain under AA supplementation, indicating absence of D6D isozyme for DPAn-6 synthesis from AA. This study demonstrated a distinct advantage of the D6D-null mice (-/-) to elucidate (1) AA function without complication of LA deprivation and (2) DHA function in the nervous system without AA depletion or DPAn-6 replacement seen in traditional models.
Division of Nutritional Sciences, Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Chad K
CK
Stroud
Takayuki Y
TY
Nara
Manuel
M
Roqueta-Rivera
Emily C
EC
Radlowski
Peter
P
Lawrence
Ying
Y
Zhang
Byung H
BH
Cho
Mariangela
M
Segre
Rex A
RA
Hess
J Thomas
JT
Brenna
Wanda M
WM
Haschek
Manabu T
MT
Nakamura
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003872:Dermatitis / Q000235:genetics; D019587:Dietary Supplements; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D006529:Hepatomegaly / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics; D007422:Intestines / Q000473:pathology*; D050602:Linoleoyl-CoA Desaturase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity; D010641:Phenotype; D012098:Reproduction / Q000235:genetics*; D012883:Skin Ulcer / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics; D014456:Ulcer / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D005231:Fatty Acids, Unsaturated; D050602:Linoleoyl-CoA Desaturase