Disruption of the Lecithin:Retinol Acyltransferase Gene Makes Mice More Susceptible to Vitamin A Deficiency

Abstract

Lecithin:retinol acyltransferase (LRAT) catalyzes the esterification of retinol (vitamin A) in the liver and in some extrahepatic tissues, including the lung. We produced an LRAT gene knock-out mouse strain and assessed whether LRAT-/- mice were more susceptible to vitamin A deficiency than wild type (WT) mice. After maintenance on a vitamin A-deficient diet for 6 weeks, the serum retinol level was 1.34 ± 0.32 μm in WT mice versus 0.13 ± 0.06 μm in LRAT-/- mice (p < 0.05). In liver, lung, eye, kidney, brain, tongue, adipose tissue, skeletal muscle, and pancreas, the retinol levels ranged from 0.05 pmol/mg (muscle and tongue) to 17.35 ± 2.66 pmol/mg (liver) in WT mice. In contrast, retinol was not detectable (<0.007 pmol/mg) in most tissues from LRAT-/- mice after maintenance on a vitamin A-deficient diet for 6 weeks. Cyp26A1 mRNA was not detected in hepatic tissue samples from LRAT-/- mice but was detected in WT mice fed the vitamin A-deficient diet. These data indicate that LRAT-/- mice are much more susceptible to vitamin A deficiency and should be an excellent animal model of vitamin A deficiency. In addition, the retinol levels in serum rapidly increased in the LRAT-/- mice upon re-addition of vitamin A to the diet, indicating that serum retinol levels in LRAT-/- mice can be conveniently modulated by the quantitative manipulation of dietary retinol. Lecithin:retinol acyltransferase (LRAT) catalyzes the esterification of retinol (vitamin A) in the liver and in some extrahepatic tissues, including the lung. We produced an LRAT gene knock-out mouse strain and assessed whether LRAT-/- mice were more susceptible to vitamin A deficiency than wild type (WT) mice. After maintenance on a vitamin A-deficient diet for 6 weeks, the serum retinol level was 1.34 ± 0.32 μm in WT mice versus 0.13 ± 0.06 μm in LRAT-/- mice (p < 0.05). In liver, lung, eye, kidney, brain, tongue, adipose tissue, skeletal muscle, and pancreas, the retinol levels ranged from 0.05 pmol/mg (muscle and tongue) to 17.35 ± 2.66 pmol/mg (liver) in WT mice. In contrast, retinol was not detectable (<0.007 pmol/mg) in most tissues from LRAT-/- mice after maintenance on a vitamin A-deficient diet for 6 weeks. Cyp26A1 mRNA was not detected in hepatic tissue samples from LRAT-/- mice but was detected in WT mice fed the vitamin A-deficient diet. These data indicate that LRAT-/- mice are much more susceptible to vitamin A deficiency and should be an excellent animal model of vitamin A deficiency. In addition, the retinol levels in serum rapidly increased in the LRAT-/- mice upon re-addition of vitamin A to the diet, indicating that serum retinol levels in LRAT-/- mice can be conveniently modulated by the quantitative manipulation of dietary retinol. Vitamin A and its derivatives (retinoids) regulate cell proliferation and differentiation. All-trans-retinoic acid (RA) 3The abbreviations used are: RAall-trans-retinoic acidCRBPcellular retinol-binding proteinCYP26cytochrome P450 retinoic acid hydroxylaseDhrs1short-chain dehydrogenase/reductase member 1ESembryonic stemHPLChigh performance liquid chromatographyLRATlecithin:retinol acyltransferasePBSphosphate-buffered salineRTreverse transcriptionWTwild typeGAPDHglyceraldehyde-3-phosphate dehydrogenase. 3The abbreviations used are: RAall-trans-retinoic acidCRBPcellular retinol-binding proteinCYP26cytochrome P450 retinoic acid hydroxylaseDhrs1short-chain dehydrogenase/reductase member 1ESembryonic stemHPLChigh performance liquid chromatographyLRATlecithin:retinol acyltransferasePBSphosphate-buffered salineRTreverse transcriptionWTwild typeGAPDHglyceraldehyde-3-phosphate dehydrogenase. is the most active retinoid (1Gudas L.J. Sporn M.B. Roberts A. Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. 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The of the dietary vitamin A is by the L. 2001; PubMed Scopus Google Scholar). the the are to which can be to the hepatic cells and R. Rev. PubMed Scopus Google Scholar, L. 2001; PubMed Scopus Google Scholar, R. J. Nutr. 2004; PubMed Google Scholar). The is of the most extrahepatic for retinol Am. J. PubMed Google Scholar, Biol. PubMed Scopus (67) Google Scholar, N. H. N. R. J. Res. Full Text PDF PubMed Google Scholar, R. J. Nutr. 2002; PubMed Scopus Google Scholar). The esterification of retinol in the liver, and to be by the lecithin:retinol acyltransferase (LRAT) and acyltransferase R. Rev. PubMed Scopus Google Scholar, J. Nutr. PubMed Google Scholar, A. A. Rando R.R. Bok D. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Full Text PDF PubMed Google Scholar, J. Biol. Full Text PDF PubMed Google Scholar). The cellular retinol-binding protein type and cellular retinol-binding protein type in the of LRAT R. Rev. PubMed Scopus Google Scholar, J. Biol. Full Text PDF PubMed Google Scholar, J. Biol. Full Text PDF PubMed Google Scholar). to and retinol to are the of and retinol to is not by retinol acyltransferase R. Rev. PubMed Scopus Google Scholar, J. Biol. Full Text PDF PubMed Google Scholar, PubMed Scopus Google Scholar, C. M. D. C. A. H. P. M. S. P. J. 1999; 18: PubMed Scopus Google Scholar). the was to esterification of retinol and the acyltransferase by M. J. Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). LRAT is increased PubMed Scopus Google Scholar, J. Biol. Full Text PDF PubMed Google Scholar, D.D. PubMed Scopus Google Scholar, J. Nutr. PubMed Scopus (47) Google Scholar). in the liver and extrahepatic tissues are for the maintenance of and retinol levels in which dietary vitamin A is R. Rev. PubMed Scopus Google Scholar, N. A. P. R. Res. PubMed Scopus Google Scholar). of vitamin A serum retinol for to N. A. P. R. Res. PubMed Scopus Google Scholar). The liver is the in which to of the retinol and in is Clin. 1996; PubMed Scopus Google Scholar, R. Rev. PubMed Scopus Google Scholar). We an LRAT gene knock-out mouse strain in which of than of the in wild type be detected in the liver and lung. These data are a Y. D. D. W. K. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google from that are in the liver and by LRAT gene We the retinol and levels in serum and in some tissues from the wild type and knock-out mice after maintenance of the mice on a vitamin A-deficient diet. that the LRAT-/- mice vitamin A-deficient in a 6 of vitamin A from their diet. the LRAT-/- mice rapidly vitamin A-deficient and many WT mice in of vitamin A deficiency. of the LRAT and the of LRAT-/- was from a mouse and was used to the gene The for the was a which was from mouse the and in the LRAT The a and a The which the for the LRAT was a gene that was by The was the and was the to the The was mouse embryonic stem cells from by a a of and of were active and A of cell were and were The that were by and were by of the and in from After the by a expression the mouse cells were by the The LRAT gene knock-out mice were from the mice that The mouse was by LRAT in a the The and and in were and A from the wild type and a from the were The expression of the LRAT gene in mouse tissues was by of Vitamin were and the were by At weeks, wild type and LRAT-/- mice were was fed the vitamin diet diet, of vitamin and the was fed a vitamin A-deficient diet samples were from the mouse and At 6 weeks, mice were and tissue samples were in the and the were of tissue samples from the liver, lung, eye, kidney, pancreas, skeletal and were and in phosphate-buffered saline of of in and The were to The were of in the X. Gudas L.J. Cancer Res. Google Scholar, X. Gudas L.J. Cancer Res. 1998; Google Scholar). The high performance liquid chromatography was a of the was an reverse and a of were X. Gudas L.J. Cancer Res. Google Scholar, X. Gudas L.J. Cancer Res. 1998; Google Scholar). The of were from the the detected the of The levels of retinol and were to the tissue tissues from the liver, lung, kidney, and were and in was the was used for reverse transcription in a from to the The produced was to of which 1 was used in a The and the of for are LRAT the and were used for and a was Cyp26A1 the and were used for and a was the dehydrogenase/reductase member 1 the and were used for and a was of are in not for the the of in and and and and protein 1 and and 1 and and and were D. M. 2001; PubMed Scopus Google Scholar). was used an for the The was the for for and for a for was from The were to The were a was The ± were of was used to in the of retinol levels The was used to a of were to be of the LRAT-/- the of the LRAT a was and the LRAT gene was by the was was by and The gene was from cell and the the were used to the LRAT gene knock-out mouse is in to the LRAT-/- mice produced by which the gene Y. D. D. W. K. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The was by The expression of LRAT mRNA in the kidney, brain, liver, and is The LRAT was in tissues in wild type mice. In contrast, expression of the LRAT gene was detected in of the tissues from LRAT-/- mice. The of the were the the a not the of the of the LRAT a was on and mice the of Cancer a of dietary vitamin A the LRAT-/- mice were the of the LRAT-/- mice the of and and In the LRAT-/- was The LRAT-/- mice the of and A but was in LRAT-/- mice. The of the are The expression in of a of genes was the mRNA level by The expression of genes in LRAT-/- tissues was to that in WT tissues These indicate that is an of in the of LRAT-/- mice but that the of not be were the wild type and LRAT-/- mice on of and in the and the retinol and levels in for retinol liver and lung, in wild type and LRAT-/- mice. These mice were fed a vitamin diet for the 6 after the are The levels of detected in the LRAT-/- and were ± and ± which were and of the in the ± pmol/mg) and ± pmol/mg) of the wild type mice and in tissues The levels of retinol and were by diet, vitamin vitamin A-deficient diet. Data are ± were samples in type type ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the are (p < from the WT mice on the was detectable in liver ± ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the were to ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the ± are (p < from the WT mice on the were from The of of was levels in the were ± ± diet ± ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the were to ± ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the ± ± ± ± are (p < from the WT mice on the was detectable in samples and ± ± ± ± ± ± ± were to ± ± ± ± ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the were to ± ± ± ± ± ± ± were to ± ± ± ± ± ± are (p < from the WT mice on the ± are (p < from the WT mice on the were to ± ± ± are (p < from the WT mice on the ± ± ± ± were to ± ± ± ± are (p < from the WT mice on the was detectable in liver were to were from The of of was levels in the were ± ± diet ± was detectable in samples and in a of the LRAT gene in a in retinol levels in the liver and lung. The retinol levels were ± pmol/mg in the and ± pmol/mg in the of the LRAT-/- which were and of the levels in the ± pmol/mg) and ± pmol/mg) of WT mice These data that the and retinol levels in tissues are in the LRAT-/- mice on a vitamin diet. in a Vitamin A-deficient whether LRAT-/- mice were more susceptible to vitamin A the wild type and LRAT-/- mice were on a vitamin diet a vitamin A-deficient diet of The of retinol in the serum was and 6 after of the vitamin A-deficient diet. The of serum retinol ranged from ± ± to ± μm in wild type mice fed the diet, in the LRAT-/- mice fed the diet ranged from ± to ± 0.06 were in the of serum retinol WT and LRAT-/- mice fed the vitamin diet (p of In wild type mice fed the vitamin A-deficient diet, the serum retinol was ± μm weeks, ± 0.32 μm weeks, and 1.34 ± 0.32 μm 6 weeks. These were not the WT mice on the vitamin diet. In contrast, LRAT-/- mice fed the vitamin A-deficient diet of serum retinol of ± μm weeks, ± 0.06 μm weeks, and 0.13 ± 0.06 μm 6 weeks. At and 6 weeks, the serum retinol was than that in WT mice on the vitamin A-deficient diet (p < The quantitative of the serum retinol are These that of the serum retinol in the LRAT-/- mice was than that in wild type mice after of the vitamin A-deficient in serum The of retinol in the serum was by The are ± type A-deficient A-deficient ± ± ± ± ± ± ± ± indicate a wild type mice on a vitamin diet, and mice on the vitamin A-deficient diet (p < ± ± ± ± indicate a wild type mice on a vitamin diet, and mice on the vitamin A-deficient diet (p < indicate a wild type mice on a vitamin diet, and mice on the vitamin A-deficient diet (p < in a of in WT and LRAT-/- a of 6 on the vitamin A-deficient diet, were from the liver, lung, eye, kidney, pancreas, adipose tissue, skeletal muscle, brain, and of wild type and LRAT-/- mice and to The levels of tissue retinol and are in The levels of and retinol in tissues from wild type and LRAT-/- fed the vitamin vitamin A-deficient diet, are from the Vitamin for 6 levels of in most extrahepatic tissues of LRAT-/- including the eye, kidney, pancreas, muscle, brain, and tongue, were than the levels in the tissues of WT mice the LRAT-/- mice were on a vitamin diet. The adipose tissue from LRAT-/- mice was the tissue type that a level of than that of WT mice ± pmol/mg in LRAT-/- versus ± pmol/mg in These data that in the LRAT-/- mice the tissues of from the Vitamin A-deficient for 6 the WT mice on a vitamin diet, the levels of in the and of WT mice to and of after fed the vitamin A-deficient diet for 6 weeks. the are in WT mice in the of dietary retinol. The levels of in tissues, including the eye, kidney, pancreas, adipose tissue, muscle, and brain, were in the WT mice on the vitamin A-deficient diet In the LRAT-/- mice of was in the of dietary vitamin A the levels are in the LRAT-/- on the vitamin and vitamin A-deficient in the for 6 the levels of retinol in the and of WT mice were than in LRAT-/- mice. The levels of retinol in the of WT mice were than in LRAT-/- mice. In contrast, the levels of retinol in most tissues, including the kidney, adipose tissue, muscle, brain, and of the WT were than the levels in the tissues of LRAT-/- mice These data indicate that LRAT is in the of the of retinol to tissues mice are fed a vitamin diet. in the Vitamin A-deficient for 6 the wild type mice retinol was detectable in tissues, from 0.05 (muscle and tongue) to 17.35 ± 2.66 pmol/mg In contrast, in the LRAT-/- retinol was detected levels in hepatic pmol/mg) and samples pmol/mg and retinol was not detectable in tissue samples These that the LRAT-/- mice are more susceptible to vitamin A deficiency and vitamin A-deficient more of retinol in tissues was in the LRAT-/- mice after 6 on the vitamin A-deficient diet in the and LRAT-/- Cyp26A1 is a cytochrome which catalyzes the of RA to J. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of Cyp26A1 gene the level of tissue retinol Y. R. FASEB J. 2000; PubMed Scopus Google Scholar). We the expression of the Cyp26A1 gene in hepatic tissue in WT and LRAT-/- mice fed data that Cyp26A1 mRNA was in the liver of LRAT-/- mice on a vitamin diet, but expression was by after the knock-out mice were fed the vitamin A-deficient diet for 6 In contrast, expression of the Cyp26A1 was in hepatic tissue from wild type mice fed the the vitamin A-deficient diet for 6 LRAT mRNA was not detectable in the hepatic samples from LRAT-/- mice LRAT mRNA levels in the of WT mice were not by the diet The expression of gene in retinol member 1999; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google was not by the LRAT gene knock-out the type of diet of Vitamin A in the Vitamin A-deficient whether the hepatic expression of the Cyp26A1 be upon the re-addition of vitamin A to the diet, a vitamin diet of vitamin was to the wild type and LRAT-/- mice that fed the vitamin A-deficient diet for 6 weeks. The expression of the Cyp26A1 in the liver was by and the of serum retinol was by after the re-addition of vitamin A to the diet. The data that the Cyp26A1 gene was in the hepatic tissues from wild type and LRAT-/- mice upon re-addition of vitamin A to the diet the serum retinol were increased in WT and LRAT-/- mice the re-addition of vitamin A to the diet These indicate that the hepatic expression level of the Cyp26A1 is the tissue retinol level in the LRAT-/- mice. We LRAT knock-out mice in to the of LRAT on the of expression of LRAT is in many types of X. Nanus D.M. Ruiz A. Rando R.R. Bok D. Gudas L.J. Cancer Res. 2001; 61: 2774-2781PubMed Google Scholar, X. Gudas L.J. Cancer Res. 1998; Google Scholar, X. D.M. Ruiz A. Bok D. Rando R.R. J.S. Nanus D.M. Gudas L.J. Cancer Res. 2002; Google Scholar, X. Ruiz A. Rando R.R. Bok D. Gudas L.J. 2000; PubMed Scopus (57) Google Scholar). In to the LRAT gene knock-out mouse strain by Y. D. D. W. K. J. 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In to the mouse LRAT-/- mice some Vitamin A deficiency can be rapidly in mice by of dietary vitamin A. by retinol levels are not in the serum but are in most tissues in LRAT-/- mice after 6 on a vitamin A-deficient diet 6 and and In addition, the retinol levels in serum rapidly in the LRAT-/- mice upon re-addition of vitamin A to the diet indicating that serum retinol levels in LRAT-/- mice can be conveniently modulated by the quantitative manipulation of dietary retinol. These the LRAT-/- mice an mouse model of vitamin A deficiency for a of and in liver and from wild type and LRAT-/- knock-out mice. The to ± The data from the LRAT-/- mice are in the and in extrahepatic tissues from wild type and LRAT-/- knock-out mice. kidney, pancreas, adipose tissue, skeletal muscle, brain, and were from mice fed a vitamin diet a vitamin A-deficient diet for 6 weeks. The to ± We used Cyp26A1 in a molecular to the retinol in the The expression of the Cyp26A1 gene is by the level of J. Nutr. PubMed Google Scholar, J. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. R. FASEB J. 2000; PubMed Scopus Google Scholar, H. S. Y. K. S. H. J. 16: PubMed Scopus Google Scholar, H. D. P. M. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). that the hepatic expression of the Cyp26A1 gene was by an of RA to dietary vitamin its expression was upon of a vitamin A-deficient diet Y. R. FASEB J. 2000; PubMed Scopus Google Scholar, M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In detected Cyp26A1 expression in wild type mice but not in the LRAT-/- mice fed a vitamin A-deficient diet These data molecular level, that LRAT-/- mice are vitamin The expression of the Cyp26A1 gene was rapidly upon of vitamin A in the diet, indicating that Cyp26A1 is a to tissue retinol levels The hepatic expression of Cyp26A1 mRNA is in the LRAT-/- mice than in WT mice fed a vitamin diet, that the expression of Cyp26A1 is in the of LRAT expression of Cyp26A1 mRNA in the and of LRAT-/- mice fed a vitamin diet is not the LRAT and genes to be to the of retinol levels J. Nutr. PubMed Google Scholar). The of the in the LRAT-/- mice that LRAT is not for the retinol but a of retinoid and levels of all-trans-retinoic acid are by in the liver and the extrahepatic tissues and of wild type and LRAT-/- mice is that in the of is to retinoic acid in a We for the LRAT-/- mice for and for