Altered vitamin A homeostasis and increased size and adiposity in the rdh1-null mouse.
Rat RoDH performs efficiently (V(m)/K(m)) in a pathway of all-trans-retinoic acid biosynthesis in cells and recognizes the physiological form of vitamin A, i.e., retinol bound with cellular retinol binding-protein, type I. Here we report that mouse embryo (e7.5 to e18.5) and liver (e12.5 to P2M) display inversely related mRNA expression of an Rodh ortholog, rdh1, and a major retinoic acid catabolic enzyme, cyp26a1, suggesting coordinate modulation of retinoic acid homeostasis. Rdh1 inactivation by homologous recombination produces mice with decreased liver cyp26a1 mRNA and protein and increased liver and kidney retinoid stores, when fed vitamin A-restricted diets. Thus, null mice autocompensate by down-regulating cyp26a1 and sparing retinoids, indicating that rdh1 metabolizes retinoids in vivo. Surprisingly, rdh1-null mice grow longer than wild type, with increased weight and adiposity, when restricted in vitamin A. Liver, kidney, and multiple fat pads increase in weight. Some differences reflect the larger sizes of rdh1-null mice, but mesentery, femoral, and inguinal fat pads grow disproportionately larger. These data reveal an unexpected contribution of Rdh1 to size and adiposity and provide the first genetic evidence of a candidate retinol dehydrogenase affecting either vitamin A-related homeostasis physiologically or vitamin A-related gene expression or biological function in vivo.
Zhang
Min
M
Nutritional Science and Toxicology, University of California, Berkeley, CA 94720-3104, USA.
Hu
Peirong
P
Krois
Charles R
CR
Kane
Maureen A
MA
Napoli
Joseph L
JL
D050154:Adiposity; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015139:Blotting, Southern; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D014801:Vitamin A / Q000378:metabolism*; D014815:Vitamins / Q000378:metabolism*; D015430:Weight Gain
D012333:RNA, Messenger; D014815:Vitamins; D014801:Vitamin A; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; C441646:Rdh1 protein, mouse; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase