Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation.
Vitamin A homoeostasis requires the gene encoding cellular retinol-binding protein-1 (Crbp1) which stimulates conversion of retinol into retinyl esters that serve as a storage form of vitamin A. The gene encoding alcohol dehydrogenase-1 (Adh1) greatly facilitates degradative metabolism of excess retinol into retinoic acid to protect against toxic effects of high dietary vitamin A. Crbp1-/-/Adh1-/- double mutant mice were generated to explore whether the stimulatory effect of CRBP1 on retinyl ester formation is due to limitation of retinol oxidation by ADH1, and whether ADH1 limits retinyl ester formation by opposing CRBP1. Compared with wild-type mice, liver retinyl ester levels were greatly reduced in Crbp1-/- mice, but Adh1-/- mice exhibited a significant increase in liver retinyl esters. Importantly, relatively normal liver retinyl ester levels were restored in Crbp1-/-/Adh1-/- mice. During vitamin A deficiency, the additional loss of Adh1 completely prevented the excessive loss of liver retinyl esters observed in Crbp1-/- mice for the first 5 weeks of deficiency and greatly minimized this loss for up to 13 weeks. Crbp1-/- mice also exhibited increased metabolism of a dose of retinol into retinoic acid, and this increased metabolism was not observed in Crbp1-/-/Adh1-/- mice. Our findings suggest that opposing actions of CRBP1 and ADH1 enable a large fraction of liver retinol to remain esterified due to CRBP1 action, while continuously allowing some retinol to be oxidized to retinoic acid by ADH1 for degradative retinoid turnover under any dietary vitamin A conditions.
Molotkov
Andrei
A
OncoDevelopmental Biology Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Ghyselinck
Norbert B
NB
Chambon
Pierre
P
Duester
Gregg
G
D000426:Alcohol Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004032:Diet; D004951:Esterification; D005838:Genotype; D006706:Homeostasis; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012177:Retinol-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054840:Retinol-Binding Proteins, Cellular; D013997:Time Factors; D014801:Vitamin A / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D014802:Vitamin A Deficiency / Q000097:blood / Q000378:metabolism
D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D014801:Vitamin A; D000426:Alcohol Dehydrogenase