title: Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue.
abstract: Approximately 80-90% of all retinoids in the body are stored as retinyl esters (REs) in the liver. Adipose tissue also contributes significantly to RE storage. The present studies, employing genetic and nutritional interventions, explored factors that are responsible for regulating RE accumulation in the liver and adipose tissue and how these influence levels of retinoic acid (RA) and RA-responsive gene expression. Our data establish that acyl-CoA:retinol acyltransferase (ARAT) activity is not involved in RE synthesis in the liver, even when mice are nutritionally stressed by feeding a 25-fold excess retinol diet or upon ablation of cellular retinol-binding protein type I (CRBPI), which is proposed to limit retinol availability to ARATs. Unlike the liver, where lecithin:retinol acyltransferase (LRAT) is responsible for all RE synthesis, this is not true for adipose tissue where Lrat-deficient mice display significantly elevated RE concentrations. However, when CrbpI is also absent, RE levels resemble wild-type levels, suggesting a role for CrbpI in RE accumulation in adipose tissue. Although expression of several RA-responsive genes is elevated in Lrat-deficient liver, employing a sensitive liquid chromatography tandem mass spectrometry protocol and contrary to what has been assumed for many years, we did not detect elevated concentrations of all-trans-RA. The elevated RA-responsive gene expression was associated with elevated hepatic triglyceride levels and decreased expression of Pparδ and its downstream Pdk4 target, suggesting a role for RA in these processes in vivo.
authors.affiliation: Institute of Human Nutrition, Columbia University, New York, NY 10032.
authors.forename: Nuttaporn
authors.initials: N
authors.lastname: Wongsiriroj
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.forename: Roseann
authors.initials: R
authors.lastname: Piantedosi
authors.forename: Kryscilla Jian Zhang
authors.initials: KJ
authors.lastname: Yang
authors.forename: Johannes
authors.initials: J
authors.lastname: Kluwe
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.forename: Henry
authors.initials: H
authors.lastname: Ginsberg
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D004822:Epididymis / Q000378:metabolism; D004951:Esterification; D004952:Esters; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047494:PPAR delta / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012176:Retinoids / Q000378:metabolism*; D051142:Retinol O-Fatty-Acyltransferase / Q000235:genetics / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C581954:CrbpI protein, mouse; D004952:Esters; D047494:PPAR delta; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012176:Retinoids; D054840:Retinol-Binding Proteins, Cellular; D014280:Triglycerides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D051142:Retinol O-Fatty-Acyltransferase; D017346:Protein Serine-Threonine Kinases
keywords: 9-cis-retinoic acid or 9-cis-RA; cellular retinol-binding protein type I; diacylglycerol acyltransferase 1; retinol-binding protein or RBP4