{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T02:20:51Z","timestamp":1777515651303,"version":"3.51.4"},"reference-count":53,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,10,15]]},"abstract":"<jats:p>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\u2212\/\u2212\/Adh1\u2212\/\u2212 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\u2212\/\u2212 mice, but Adh1\u2212\/\u2212 mice exhibited a significant increase in liver retinyl esters. Importantly, relatively normal liver retinyl ester levels were restored in Crbp1\u2212\/\u2212\/Adh1\u2212\/\u2212 mice. During vitamin A deficiency, the additional loss of Adh1 completely prevented the excessive loss of liver retinyl esters observed in Crbp1\u2212\/\u2212 mice for the first 5\u00a0weeks of deficiency and greatly minimized this loss for up to 13\u00a0weeks. Crbp1\u2212\/\u2212 mice also exhibited increased metabolism of a dose of retinol into retinoic acid, and this increased metabolism was not observed in Crbp1\u2212\/\u2212\/Adh1\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1042\/bj20040621","type":"journal-article","created":{"date-parts":[[2004,10,8]],"date-time":"2004-10-08T11:33:06Z","timestamp":1097235186000},"page":"295-302","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation"],"prefix":"10.1042","volume":"383","author":[{"given":"Andrei","family":"MOLOTKOV","sequence":"first","affiliation":[{"name":"OncoDevelopmental Biology Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert\u00a0B.","family":"GHYSELINCK","sequence":"additional","affiliation":[{"name":"Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS\/INSERM\/Universite Louis Pasteur, College de France, 67404 Illkirch Cedex, Communaute Urbaine de Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"CHAMBON","sequence":"additional","affiliation":[{"name":"Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS\/INSERM\/Universite Louis Pasteur, College de France, 67404 Illkirch Cedex, Communaute Urbaine de Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregg","family":"DUESTER","sequence":"additional","affiliation":[{"name":"OncoDevelopmental Biology Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2004,10,8]]},"reference":[{"key":"2021112217030600300_B1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1126\/science.113.2933.287","article-title":"The chemistry of rod vision","volume":"113","author":"Wald","year":"1951","journal-title":"Science"},{"key":"2021112217030600300_B2","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/0092-8674(95)90202-3","article-title":"Nonsteroid nuclear receptors: What are genetic studies telling us about their role in real life?","volume":"83","author":"Kastner","year":"1995","journal-title":"Cell"},{"key":"2021112217030600300_B3","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1093\/jn\/131.3.705","article-title":"Function of vitamin A in vertebrate embryonic development","volume":"131","author":"Zile","year":"2001","journal-title":"J. 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Biophys."},{"key":"2021112217030600300_B11","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1101\/gad.5.8.1333","article-title":"Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis","volume":"5","author":"Rossant","year":"1991","journal-title":"Genes Dev."},{"key":"2021112217030600300_B12","first-page":"257","article-title":"Plasma retinol-binding protein","volume-title":"The Retinoids: Biology, Chemistry, and Medicine","author":"Soprano","year":"1994","edition":"2nd edition"},{"key":"2021112217030600300_B13","doi-asserted-by":"crossref","first-page":"4633","DOI":"10.1093\/emboj\/18.17.4633","article-title":"Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein","volume":"18","author":"Quadro","year":"1999","journal-title":"EMBO J."},{"key":"2021112217030600300_B14","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1161\/01.RES.0000069030.30886.8F","article-title":"Increased fibronectin deposition in embryonic hearts of retinol-binding protein-null mice","volume":"92","author":"Wendler","year":"2003","journal-title":"Circ. 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Chem."},{"key":"2021112217030600300_B17","first-page":"283","article-title":"Cellular retinoid-binding proteins","volume-title":"The Retinoids: Biology, Chemistry, and Medicine","author":"Ong","year":"1994","edition":"2nd edition"},{"key":"2021112217030600300_B18","doi-asserted-by":"crossref","first-page":"4903","DOI":"10.1093\/emboj\/18.18.4903","article-title":"Cellular retinol-binding protein I is essential for vitamin A homeostasis","volume":"18","author":"Ghyselinck","year":"1999","journal-title":"EMBO J."},{"key":"2021112217030600300_B19","doi-asserted-by":"crossref","first-page":"5337","DOI":"10.1073\/pnas.082093299","article-title":"Stimulation of retinoic acid production and growth by ubiquitously-expressed alcohol dehydrogenase Adh3","volume":"99","author":"Molotkov","year":"2002","journal-title":"Proc. Natl. Acad. Sci. 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Chem."},{"key":"2021112217030600300_B35","doi-asserted-by":"crossref","first-page":"4637","DOI":"10.1128\/MCB.23.13.4637-4648.2003","article-title":"Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina","volume":"23","author":"Fan","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2021112217030600300_B36","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/dvdy.10292","article-title":"Retinoic acid signalling centres in the avian embryo identified by sites of expression of synthesising and catabolising enzymes","volume":"227","author":"Blentic","year":"2003","journal-title":"Dev. Dyn."},{"key":"2021112217030600300_B37","doi-asserted-by":"crossref","first-page":"14036","DOI":"10.1073\/pnas.2336223100","article-title":"A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment","volume":"100","author":"Dup\u00e9","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112217030600300_B38","first-page":"427","article-title":"Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal","volume":"41","author":"Roberts","year":"1992","journal-title":"Mol. Pharmacol."},{"key":"2021112217030600300_B39","doi-asserted-by":"crossref","first-page":"29922","DOI":"10.1074\/jbc.271.47.29922","article-title":"Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase","volume":"271","author":"White","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021112217030600300_B40","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/ng876","article-title":"Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development","volume":"31","author":"Niederreither","year":"2002","journal-title":"Nat. Genet."},{"key":"2021112217030600300_B41","doi-asserted-by":"crossref","first-page":"36085","DOI":"10.1074\/jbc.M303709200","article-title":"Genetic evidence that retinaldehyde dehydrogenase Raldh1 (Aldh1a1) functions downstream of alcohol dehydrogenase Adh1 in metabolism of retinol to retinoic acid","volume":"278","author":"Molotkov","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112217030600300_B42","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0168-8278(98)80200-6","article-title":"Human hepatic stellate cells express class I alcohol dehydrogenase and aldehyde dehydrogenase but not cytochrome P4502E1","volume":"28","author":"Casini","year":"1998","journal-title":"J. Hepatol."},{"key":"2021112217030600300_B43","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1096\/fasebj.7.2.8440409","article-title":"Cellular metabolism and activation of retinoids: Roles of cellular retinoid-binding proteins","volume":"7","author":"Ross","year":"1993","journal-title":"FASEB J."},{"key":"2021112217030600300_B44","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S1388-1981(99)00117-1","article-title":"Interactions of retinoid binding proteins and enzymes in retinoid metabolism","volume":"1440","author":"Napoli","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112217030600300_B45","doi-asserted-by":"crossref","first-page":"16796","DOI":"10.1074\/jbc.274.24.16796","article-title":"Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice: Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid","volume":"274","author":"Deltour","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112217030600300_B46","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1007\/BF01981505","article-title":"4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse","volume":"66","author":"Collins","year":"1992","journal-title":"Arch. Toxicol."},{"key":"2021112217030600300_B47","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1095\/biolreprod46.5.802","article-title":"Developmental changes in endogenous retinoids during pregnancy and embryogenesis in the mouse","volume":"46","author":"Satre","year":"1992","journal-title":"Biol. Reprod."},{"key":"2021112217030600300_B48","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1432-1033.1983.tb07807.x","article-title":"Purification and molecular properties of mouse alcohol dehydrogenase isozymes","volume":"137","author":"Algar","year":"1983","journal-title":"Eur. J. Biochem."},{"key":"2021112217030600300_B49","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/B978-0-12-658102-7.50011-7","article-title":"Metabolism of retinoids","volume-title":"The Retinoids, vol. 2","author":"Frolik","year":"1984"},{"key":"2021112217030600300_B50","first-page":"545","article-title":"General and reproductive toxicology of retinoids","volume-title":"The Retinoids: Biology, Chemistry, and Medicine","author":"Armstrong","year":"1994","edition":"2nd edition"},{"key":"2021112217030600300_B51","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1006\/taap.2001.9170","article-title":"Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: Mechanistic studies","volume":"173","author":"Bray","year":"2001","journal-title":"Toxicol. Appl. 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