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1.
J Lipid Res ; 55(1): 104-14, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24186946

RESUMO

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.


Assuntos
Tecido Adiposo Branco/metabolismo , Fígado/metabolismo , Retinoides/metabolismo , Animais , Epididimo/metabolismo , Esterificação , Ésteres , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR delta/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Retinol O-Graxo-Aciltransferase/genética , Retinol O-Graxo-Aciltransferase/metabolismo , Proteínas Celulares de Ligação ao Retinol/genética , Proteínas Celulares de Ligação ao Retinol/metabolismo , Triglicerídeos/metabolismo
2.
J Biol Chem ; 284(7): 4292-9, 2009 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-19028692

RESUMO

Retinoic acid (RA) is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. The synthesis of RA from its precursor retinol (vitamin A) is an important regulatory mechanism. Therefore, the esterification of retinol with fatty acyl moieties to generate retinyl esters, the main storage form of retinol, may also regulate RA levels. Here we show that the neutral lipid synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) functions as the major acyl-CoA:retinol acyltransferase (ARAT) in murine skin. When dietary retinol is abundant, DGAT1 deficiency results in elevated levels of RA in skin and cyclical hair loss; both are prevented by dietary retinol deprivation. Further, DGAT1-deficient skin exhibits enhanced sensitivity to topically administered retinol. Deletion of the enzyme specifically in the epidermis causes alopecia, indicating that the regulation of RA homeostasis by DGAT1 is autonomous in the epidermis. These findings show that DGAT1 functions as an ARAT in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity. Our findings may have implications for human skin or hair disorders treated with agents that modulate RA signaling.


Assuntos
Diacilglicerol O-Aciltransferase/metabolismo , Epiderme/enzimologia , Homeostase/fisiologia , Retinol O-Graxo-Aciltransferase/metabolismo , Tretinoína/metabolismo , Alopecia/enzimologia , Alopecia/genética , Animais , Diacilglicerol O-Aciltransferase/genética , Feminino , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Retinoides/genética , Retinoides/metabolismo , Retinol O-Graxo-Aciltransferase/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tretinoína/farmacologia
3.
Exp Eye Res ; 82(1): 111-21, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16054134

RESUMO

Visual perception is mediated by a family of G protein-coupled receptors called the opsins. The light-absorbing chromophore in most opsins is 11-cis-retinaldehyde, which is isomerized to all-trans-retinaldehyde upon absorption of a photon. Restoration of light sensitivity to the photobleached opsin requires chemical re-isomerization of the chromophore. This is carried out by an enzymatic pathway called the visual cycle in retinal pigment epithelial cells. The isomerase in this pathway uses fatty-acyl esters of all-trans-retinol as substrate. A retinyl-ester synthase that produces these esters, called lecithin:retinol acyltransferase (LRAT), has been extensively characterized. Based on prior biochemical studies and the phenotype in lrat(-/-) knockout mice, it has been assumed that LRAT is the sole or dominant retinyl-ester synthase in the retinal pigment epithelium. Here we demonstrate the presence of a second ester synthase activity in these cells called acyl CoA:retinol acyltransferase (ARAT). We show that this activity uses palmitoyl coenzyme A as an acyl donor, unlike LRAT which uses phosphatidylcholine. Similar to LRAT, ARAT esterifies both all-trans-retinol and 11-cis-retinol. LRAT and ARAT are both potently inhibited by the retinyl-ester analog, all-trans-retinylbromoacetate, but only ARAT is inhibited by progesterone. Unexpectedly, the maximum turnover rate (V(max)) of ARAT was similar to that of LRAT. However, the Michaelis constant (K(M)) of ARAT was 10-fold higher than the K(M) of LRAT for all-trans-retinol. These observations suggest that ARAT may complement LRAT to provide additional retinyl-ester synthase activity under conditions of high all-trans-retinol. These conditions occur in the retina following exposure to bright light.


Assuntos
Epitélio Pigmentado Ocular/enzimologia , Retinol O-Graxo-Aciltransferase/análise , Aciltransferases/metabolismo , Animais , Bovinos , Linhagem Celular , Membrana Celular/química , Clonagem Molecular , Humanos , Immunoblotting , Camundongos , Microssomos/química , Palmitoil Coenzima A/farmacologia , Retinol O-Graxo-Aciltransferase/genética , Estimulação Química , Transfecção/métodos
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