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Increased adiposity in the retinol saturase-knockout mouse.

ABSTRACT: The enzyme retinol saturase (RetSat) catalyzes the saturation of all-trans-retinol to produce (R)-all-trans-13,14-dihydroretinol. As a peroxisome proliferator-activated receptor (PPAR) gamma target, RetSat was shown to be required for adipocyte differentiation in the 3T3-L1 cell culture model. To understand the mechanism involved in this putative proadipogenic effect of RetSat, we studied the consequences of ablating RetSat expression on retinoid metabolism and adipose tissue differentiation in RetSat-null mice. Here, we report that RetSat-null mice have normal levels of retinol and retinyl palmitate in liver, serum, and adipose tissue, but, in contrast to wild-type mice, are deficient in the production of all-trans-13,14-dihydroretinol from dietary vitamin A. Despite accumulating more fat, RetSat-null mice maintained on either low-fat or high-fat diets gain weight and have similar rates of food intake as age- and gender-matched wild-type control littermates. This increased adiposity of RetSat-null mice is associated with up-regulation of PPARgamma, a key transcriptional regulator of adipogenesis, and also its downstream target, fatty acid-binding protein 4 (FABP4/aP2). On the basis of these results, we propose that dihydroretinoids produced by RetSat control physiological processes that influence PPARgamma activity and regulate lipid accumulation in mice.-Moise, A. R., Lobo, G. P., Erokwu, B., Wilson, D. L., Peck, D., Alvarez, S., Domínguez, M., Alvarez, R., Flask, C. A., de Lera, A. R., von Lintig, J., Palczewski, K. Increased adiposity in the retinol saturase-knockout mouse.

SUBMITTER: Moise AR

PROVIDER: S-EPMC2845435 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Increased adiposity in the retinol saturase-knockout mouse.

Moise Alexander R AR Lobo Glenn P GP Erokwu Bernadette B Wilson David L DL Peck David D Alvarez Susana S Domínguez Marta M Alvarez Rosana R Flask Chris A CA de Lera Angel R AR von Lintig Johannes J Palczewski Krzysztof K

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20091125 4

The enzyme retinol saturase (RetSat) catalyzes the saturation of all-trans-retinol to produce (R)-all-trans-13,14-dihydroretinol. As a peroxisome proliferator-activated receptor (PPAR) gamma target, RetSat was shown to be required for adipocyte differentiation in the 3T3-L1 cell culture model. To understand the mechanism involved in this putative proadipogenic effect of RetSat, we studied the consequences of ablating RetSat expression on retinoid metabolism and adipose tissue differentiation in ...[more]

PMID: 19940255

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Project description:Metabolism of vitamin A, all-trans-retinol, leads to the formation of 11-cis-retinaldehyde, the visual chromophore, and all-trans-retinoic acid, which is involved in the regulation of gene expression through the retinoic acid receptor. Enzymes and binding proteins involved in retinoid metabolism are highly conserved across species. We previously described a novel mammalian enzyme that saturates the 13-14 double bond of all-trans-retinol to produce all-trans-13,14-dihydroretinol, which then follows the same metabolic fate as that of all-trans-retinol. Specifically, all-trans-13,14-dihydroretinol is transiently oxidized to all-trans-13,14-dihydroretinoic acid before being oxidized further by Cyp26 enzymes. Here, we report the identification of two putative RetSat homologues in zebrafish, one of which, zebrafish RetSat A (zRetSat A), also had retinol saturase activity, whereas zebrafish RetSat B (zRetSat B) was inactive under similar conditions. Unlike mouse RetSat (mRetSat), zRetSat A had an altered bond specificity saturating either the 13-14 or 7-8 double bonds of all-trans-retinol to produce either all-trans-13,14-dihydroretinol or all-trans-7,8-dihydroretinol, respectively. zRetSat A also saturated the 13-14 or 7-8 double bonds of all-trans-3,4-didehydroretinol (vitamin A2), a second endogenous form of vitamin A in zebrafish. The dual enzymatic activity of zRetSat A displays a newly acquired specificity for the 13-14 double bond retained in higher vertebrates and also the evolutionarily preserved activity of bacterial phytoene desaturases and plant carotenoid isomerases. Expression of zRetSat A was restricted to the liver and intestine of hatchlings and adult zebrafish, whereas zRetSat B was expressed in the same tissues but at earlier developmental stages. Exogenous all-trans-retinol, all-trans-13,14-dihydroretinol, or all-trans-7,8-dihydroretinol led to the strong induction of the expression of the retinoic acid-metabolizing enzyme, Cyp26A1, arguing for an active signaling function of dihydroretinoid metabolites in zebrafish. These findings point to a conserved function but altered specificity of RetSat in vertebrates, leading to the generation of various dihydroretinoid compounds, some of which could have signaling functions.

Dataset Information

Increased adiposity in the retinol saturase-knockout mouse.

Publications

Increased adiposity in the retinol saturase-knockout mouse.

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