Identification of All-trans-Retinol:All-trans-13,14-dihydroretinol Saturase

Moise, Alexander R.; Kuksa, Vladimir; Imanishi, Yoshikazu; Palczewski, Krzysztof

doi:10.1074/jbc.m409130200

Cited by 98 publications

(123 citation statements)

References 62 publications

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“…RetSat has been shown to catalyze the conversion of retinol to 13,14-dhretinol (16), and thus we hypothesized that this retinoid would rescue the effect of RetSat ablation during differentiation. Surprisingly, however, 13,14-dhretinol did not compensate for the effect of RetSat ablation (Fig.…”

Section: Retsat Is Required For Normal Adipocyte Differentiation Downmentioning

confidence: 99%

“…In the search for missing pieces of adipose retinoid metabolism, we found that the oxidoreductase retinol saturase (RetSat), which has been described to catalyze the reaction of retinol to 13,14-dihydroretinol (dhretinol) (16), is induced during murine and human fat cell differentiation. RetSat expression is controlled by PPAR␥ through an intronic PPAR␥ response element (PPRE) in adipocytes.…”

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confidence: 99%

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Retinol saturase promotes adipogenesis and is downregulated in obesity

Schupp

Lefterova

Janke

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Adipocyte differentiation is controlled by many transcription factors, but few known downstream targets of these factors are necessary for adipogenesis. Here we report that retinol saturase (RetSat), which is an enzyme implicated in the generation of dihydroretinoid metabolites, is induced during adipogenesis and is directly regulated by the transcription factor peroxisome proliferator activated receptor γ (PPARγ). Ablation of RetSat dramatically inhibited adipogenesis but, surprisingly, this block was not overcome by the putative product of RetSat enzymatic activity. On the other hand, ectopic RetSat with an intact, but not a mutated, FAD/NAD dinucleotide-binding motif increased endogenous PPARγ transcriptional activity and promoted adipogenesis. Indeed, RetSat was not required for adipogenesis when cells were provided with exogenous PPARγ ligands. In adipose tissue, RetSat is expressed in adipocytes but is unexpectedly downregulated in obesity, most likely owing to infiltration of macrophages that we demonstrate to repress RetSat expression. Thiazolidinedione treatment reversed low RetSat expression in adipose tissue of obese mice. Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease.

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Section: Retsat Is Required For Normal Adipocyte Differentiation Downmentioning

confidence: 99%

mentioning

confidence: 99%

Retinol saturase promotes adipogenesis and is downregulated in obesity

Schupp

Lefterova

Janke

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to these cellular events, adipose tissue and renal physiology may also be altered as suggested by the response of a retinol saturase enzyme (RetSat, all-trans-retinol reductase) that has a > 2-fold increase in expression and by the > 2-fold repression of a Na + /H + exchange regulatory factor (NHE-RF1). RetSat is probably involved in vitamin A (or retinol) metabolism and adipose tissue physiology through adipocyte differentiation (Moise et al 2004(Moise et al , 2010. The lack of knowledge about this role precludes any further interpretation regarding a potential alteration of retinoid metabolism or adipose tissue physiology.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France

Bertucci

Pierron

Thébault

et al. 2017

Environ Sci Pollut Res

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The freshwater pearl mussel Margaritifera margaritifera is one of the most threatened freshwater bivalves worldwide. In this study, we aimed (i) to study the processes by which water quality might affect freshwater mussels in situ and (ii) to provide insights into the ecotoxicological significance of water pollution to natural populations in order to provide necessary information to enhance conservation strategies. M. margaritifera specimens were sampled in two close sites located upstream or downstream from an illegal dumping site. The renal transcriptome of these animals was assembled and gene transcription determined by RNA-seq. Correlations between transcription levels of each single transcript and the bioaccumulation of nine trace metals, age (estimated by sclerochronology), and condition index were determined in order to identify genes likely to respond to a specific factor. Amongst the studied metals, Cr, Zn, Cd, and Ni were the main factors correlated with transcription levels, with effects on translation, apoptosis, immune response, response to stimulus, and transport pathways.However, the main factor explaining changes in gene transcription appeared to be the age of individuals with a negative correlation with the transcription of retrotransposon-related genes. To investigate this effect further, mussels were classified into three age classes. In young, middle-aged and old animals, transcription levels were mainly explained by Cu, Zn and age, respectively. This suggests differences in the molecular responses of this species to metals during its lifetime that must be better assessed in future ecotoxicology studies.

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“…Reactions were carried out at 30°C for 2 min and then quenched by the addition of 100 l of methanol. Retinoids were extracted with 200 l of hexane and analyzed on a HewlettPackard 1100 series HPLC system equipped with a diode array detector and a Beckman Ultrasphere Si normal-phase column (5 m, 4.5 ϫ 250 mm) (32). The initial velocity data were analyzed using the Michaelis-Menten equation by nonlinear regression analysis.…”

Section: Methodsmentioning

confidence: 99%

“…We transiently transfected COS-7 cells to study the targeting and distribution of WT LRAT and its truncation mutants. Formation of retinosomes (retinyl ester storage particles) was studied in vitro in stably transfected HEKK-LRAT cells, which express mouse WT LRAT under the control of a tetracycline-inducible promoter (32). Cells were cultured in complete Dulbecco's modified Eagle's medium on glass-bottom microwell dishes (MatTek Corp., Ashland, MA).…”

Section: Methodsmentioning

confidence: 99%

Topology and Membrane Association of Lecithin: Retinol Acyltransferase

Moise

Golczak

Imanishi

et al. 2007

Journal of Biological Chemistry

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Fatty acid retinyl esters are the storage form of vitamin A (alltrans-retinol) and serve as metabolic intermediates in the formation of the visual chromophore 11-cis-retinal. Lecithin:retinol acyltransferase (LRAT), the main enzyme responsible for retinyl ester formation, acts by transferring an acyl group from the sn-1 position of phosphatidylcholine to retinol. To define the membrane association and localization of LRAT, we produced an LRAT-specific monoclonal antibody, which we used to study enzyme partition under different experimental conditions. Furthermore, we examined the membrane topology of LRAT through an N-linked glycosylation scanning approach and protease protection assays. We show that LRAT is localized to the membrane of the endoplasmic reticulum (ER) and assumes a single membrane-spanning topology with an N-terminal cytoplasmic/C-terminal luminal orientation. In eukaryotic cells, the C-terminal transmembrane domain is essential for the activity and ER membrane targeting of LRAT. In contrast, the N-terminal hydrophobic region is not required for ER membrane targeting or enzymatic activity, and its amino acid sequence is not conserved in other species examined. We present experimental evidence of the topology and subcellular localization of LRAT, a critical enzyme in vitamin A metabolism.The metabolism of vitamin A (all-trans-retinol) leads to the formation of all-trans-retinoic acid and 11-cis-retinal derivatives that play crucial roles in such processes as development, immunity, and vision (1-6). Recent studies have highlighted the importance of lecithin:retinol acyltransferase (LRAT) 3 in the absorption and retention of retinol in intracellular stores (7). LRAT catalyzes the synthesis of retinyl esters, thereby drawing retinol from the circulation to storage depots such as the lipid droplets of hepatic stellate cells and the retinosome structures found in the retinal pigment epithelium (RPE) (8, 9). Mutations in the LRAT gene lead to early-onset severe retinal dystrophy (10). Disruption of the Lrat gene in Lrat Ϫ/Ϫ mice produces a severe impairment in retinol uptake and storage capacity. As a result, Lrat Ϫ/Ϫ mice are blind (11) and more susceptible to vitamin A deficiency than their wild-type (WT) counterparts (12). Lrat Ϫ/Ϫ mice possess only trace amounts of retinyl esters in most tissues (11, 12), yet, surprisingly, the levels of retinyl esters in their adipose tissue are elevated compared with those in WT mice (12). Adipose stores of retinyl esters could depend on the activity of acyl-CoA:retinol acyltransferase (12).LRAT plays a pivotal role in determining retinol availability, which in turn affects the levels of all-trans-retinoic acid, a potent regulator of the expression of many genes via retinoic acid receptors (13). Expression of LRAT in the liver is influenced by multiple factors, including vitamin A status (14), retinoic acid (15), other synthetic retinoic acid receptor activators (16), and peroxisome proliferator-activated receptor ␤/␦ agonists (17). Thus, regulation of LRAT activi...

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Identification of All-trans-Retinol:All-trans-13,14-dihydroretinol Saturase

Cited by 98 publications

References 62 publications

Retinol saturase promotes adipogenesis and is downregulated in obesity

Retinol saturase promotes adipogenesis and is downregulated in obesity

Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France

Topology and Membrane Association of Lecithin: Retinol Acyltransferase

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