Retinyl Ester Formation by Lecithin:Retinol Acyltransferase Is a Key Regulator of Retinoid Homeostasis in Mouse Embryogenesis

Vitamin A (VA) plays an important role in post-natal lung development and maturation. Previously, we have reported that a supplemental dose of VA combined with 10 % of all-trans-retinoic acid (VARA) synergistically increases retinol uptake and retinyl ester (RE) storage in neonatal rat lung, while up-regulating several retinoid homeostatic genes including lecithin:retinol acyltransferase (LRAT) and the retinol-binding protein receptor, stimulated by retinoic acid 6 (STRA6). However, whether inflammation has an impact on the expression of these genes and thus compromises the ability of VARA to increase lung RE content is not clear. Neonatal rats, 7- to 8-d-old, were treated with VARA either concurrently with lipopolysaccharide (LPS; Expt 1) or 12 h after LPS administration (Expt 2); in both studies, lung tissue was collected 6 h after VARA treatment, when RE formation is maximal. Inflammation was confirmed by increased IL-6 and chemokine (C–C motif) ligand 2 (CCL2) gene expression in lung at 6 h and C-reactive protein in plasma at 18 h. In both studies, LPS-induced inflammation only slightly reduced, but did not prevent the VARA-induced increase in lung RE. Quantitative RT-PCR showed that co-administration of LPS with VARA slightly attenuated the VARA-induced increase of LRAT mRNA, but not of STRA6 or cytochrome P450 26B1, the predominant RA hydroxylase in lung. By 18 h post-LPS, expression had subsided and none of these genes differed from the level in the control group. Overall, the present results suggest that retinoid homeostatic gene expression is reduced modestly, if at all, by acute LPS-induced inflammation and that VARA is still effective in increasing lung RE under conditions of moderate inflammation.

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Multiple pathways ensure retinoid delivery to milk: studies in genetically modified mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00491.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. E862-E870 ◽

Cited By ~ 17

Author(s):

Sheila M. O'Byrne ◽

Yuko Kako ◽

Richard J. Deckelbaum ◽

Inge H. Hansen ◽

Krzysztof Palczewski ◽

...

Keyword(s):

Normal Growth ◽

Retinyl Palmitate ◽

Postnatal Period ◽

Retinol Binding Protein ◽

Wild Type ◽

Retinyl Ester ◽

Ester Formation ◽

Fatty Acid Transporter ◽

Retinyl Esters ◽

Lecithin:Retinol Acyltransferase

Retinoids are absolutely required for normal growth and development during the postnatal period. We studied the delivery of retinoids to milk, availing of mouse models modified for proteins thought to be essential for this process. Milk retinyl esters were markedly altered in mice lacking the enzyme lecithin:retinol acyltransferase ( Lrat−/−), indicating that this enzyme is normally responsible for the majority of retinyl esters incorporated into milk and not an acyl-CoA dependent enzyme, as proposed in the literature. Unlike wild-type milk, much of the retinoid in Lrat−/− milk is unesterified retinol, not retinyl ester. The composition of the residual retinyl ester present in Lrat−/− milk was altered from predominantly retinyl palmitate and stearate to retinyl oleate and medium chain retinyl esters. This was accompanied by increased palmitate and decreased oleate in Lrat−/− milk triglycerides. In other studies, we investigated the role of retinol-binding protein in retinoid delivery for milk formation. We found that Rbp−/− mice maintain milk retinoid concentrations similar to those in matched wild-type mice. This appears to arise due to greater postprandial delivery of retinoid, a lipoprotein lipase (LPL)-dependent pathway. Importantly, LPL also acts to assure delivery of long-chain fatty acids (LCFA) to milk. The fatty acid transporter CD36 also facilitated LCFA but not retinoid incorporation into milk. Our data show that compensatory pathways for the delivery of retinoids ensure their optimal delivery and that LRAT is the most important enzyme for milk retinyl ester formation.

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Inhibitors of retinyl ester formation also prevent the biosynthesis of 11-cis-retinol

Biochemistry ◽

10.1021/bi00454a001 ◽

1990 ◽

Vol 29 (2) ◽

pp. 309-312 ◽

Cited By ~ 50

Author(s):

Achla Trehan ◽

Francisco J. Canada ◽

Robert R. Rando

Keyword(s):

Retinyl Ester ◽

Ester Formation

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Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats

The Journal of Lipid Research ◽

10.1194/jlr.m600061-jlr200 ◽

2006 ◽

Vol 47 (8) ◽

pp. 1844-1851 ◽

Cited By ~ 36

Author(s):

A. Catharine Ross ◽

Namasivayam Ambalavanan ◽

Reza Zolfaghari ◽

Nan-qian Li

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Neonatal Rats ◽

Retinyl Ester ◽

Ester Formation

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Acidic retinoids in small amounts promote retinyl ester formation in neonatal lung, with transient increases in retinoid homeostatic gene expression

Nutrition & Metabolism ◽

10.1186/1743-7075-10-72 ◽

2013 ◽

Vol 10 (1) ◽

pp. 72 ◽

Cited By ~ 5

Author(s):

Lili Wu ◽

Reza Zolfaghari ◽

A Ross

Keyword(s):

Gene Expression ◽

Retinyl Ester ◽

Ester Formation ◽

Neonatal Lung

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Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation

Biochemical Journal ◽

10.1042/bj20040621 ◽

2004 ◽

Vol 383 (2) ◽

pp. 295-302 ◽

Cited By ~ 34

Author(s):

Andrei MOLOTKOV ◽

Norbert B. GHYSELINCK ◽

Pierre CHAMBON ◽

Gregg DUESTER

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Alcohol Dehydrogenase ◽

Retinol Binding Protein ◽

Dietary Vitamin ◽

Gene Encoding ◽

Retinyl Ester ◽

Ester Formation ◽

Retinyl Esters ◽

Cellular Retinol Binding Protein

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−/−/Adh1−/− 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−/− mice, but Adh1−/− mice exhibited a significant increase in liver retinyl esters. Importantly, relatively normal liver retinyl ester levels were restored in Crbp1−/−/Adh1−/− mice. During vitamin A deficiency, the additional loss of Adh1 completely prevented the excessive loss of liver retinyl esters observed in Crbp1−/− mice for the first 5 weeks of deficiency and greatly minimized this loss for up to 13 weeks. Crbp1−/− mice also exhibited increased metabolism of a dose of retinol into retinoic acid, and this increased metabolism was not observed in Crbp1−/−/Adh1−/− 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.

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Lecithin:Retinol Acyltransferase and Retinyl Ester Hydrolase Activities Are Differentially Regulated by Retinoids and Have Distinct Distributions between Hepatocyte and Nonparenchymal Cell Fractions of Rat Liver

Journal of Nutrition ◽

10.1093/jn/127.2.218 ◽

1997 ◽

Vol 127 (2) ◽

pp. 218-224 ◽

Cited By ~ 41

Author(s):

Tomokazu Matsuura ◽

Mohamed Z. Gad ◽

Earl H. Harrison ◽

A. Catharine Ross

Keyword(s):

Rat Liver ◽

Retinyl Ester ◽

Ester Hydrolase ◽

Retinyl Ester Hydrolase ◽

Lecithin:Retinol Acyltransferase ◽

Cell Fractions

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Retinol esterification in bovine retinal pigment epithelium: reversibility of lecithin:retinol acyltransferase

Biochemical Journal ◽

10.1042/bj2910697 ◽

1993 ◽

Vol 291 (3) ◽

pp. 697-700 ◽

Cited By ~ 40

Author(s):

J C Saari ◽

D L Bredberg ◽

D F Farrell

Keyword(s):

Retinal Pigment Epithelium ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Isomerization Reaction ◽

Ester Synthesis ◽

Exchange Reactions ◽

Geometrical Isomers ◽

Retinyl Ester ◽

Progress Curve ◽

Lecithin:Retinol Acyltransferase

Esterification of all-trans-retinol is a key reaction of the vertebrate visual cycle, since it produces an insoluble, relatively non-toxic, form of the vitamin for storage and supplies substrate for the isomerization reaction. CoA-dependent and -independent pathways have been described for retinol esterification in retinal pigment epithelium (RPE). The CoA-independent reaction, catalysed by lecithin:retinol acyltransferase (LRAT) was examined in more detail in this study. Addition of retinol to RPE microsomes results in a burst of retinyl ester synthesis, followed by a rapid apparent cessation of the reaction. However, [3H]retinol, added when retinyl ester synthesis has apparently ceased, is rapidly incorporated into retinyl ester without a net increase in the amount of ester. The specific radioactivities of [3H]retinol and [3H]retinyl ester reach the same value. [14C]Palmitate from palmitoyl-CoA is incorporated into preexisting retinyl ester in the absence of net ester synthesis, too. These exchange reactions suggest that the reaction has reached equilibrium at the plateau of the progress curve and that only the accumulation of retinyl ester, and not its synthesis, has stopped during this phase of the reaction. Studies with geometrical isomers of retinol revealed that the rate of exchange of all-trans-retinol with all-trans-retinyl esters was about 6 times more rapid than exchange of 11-cis-retinol with 11-cis-retinyl ester. This is the first demonstration of the reversibility of LRAT and the first example of stereospecificity of retinyl ester synthesis in the visual system. Reversal of the LRAT reaction could contribute to the mobilization of 11-cis-retinol from 11-cis-retinyl ester pools.

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