Abstract

Lecithin:retinol acyltransferase (LRAT) is believed to be the predominant if not the sole enzyme in the body responsible for the physiologic esterification of retinol. We have studied Lrat-deficient (Lrat-/-) mice to gain a better understanding of how these mice take up and store dietary retinoids and to determine whether other enzymes may be responsible for retinol esterification in the body. Although the Lrat-/- mice possess only trace amounts of retinyl esters in liver, lung, and kidney, they possess elevated (by 2-3-fold) concentrations of retinyl esters in adipose tissue compared with wild type mice. These adipose retinyl ester depots are mobilized in times of dietary retinoid insufficiency. We further observed an up-regulation (3-4-fold) in the level of cytosolic retinol-binding protein type III (CRBPIII) in adipose tissue of Lrat-/- mice. Examination by electron microscopy reveals a striking total absence of large lipid-containing droplets that normally store hepatic retinoid within the hepatic stellate cells of Lrat-/- mice. Despite the absence of significant retinyl ester stores and stellate cell lipid droplets, the livers of Lrat-/- mice upon histologic analysis appear normal and show no histological signs of liver fibrosis. Lrat-/- mice absorb dietary retinol primarily as free retinol in chylomicrons; however, retinyl esters are also present within the chylomicron fraction obtained from Lrat-/- mice. The fatty acyl composition of these (chylomicron) retinyl esters suggests that they are synthesized via an acyl-CoA-dependent process suggesting the existence of a physiologically significant acyl-CoA:retinol acyltransferase.

Highlights

  • Latory activities of retinoids are thought to result from the actions of all-trans- and 9-cis-retinoic acid (6 – 8)

  • Tissue Retinoic Acid Levels Are Not Different for Wild Type and LratϪ/Ϫ Mice—Because retinyl ester levels in tissues of LratϪ/Ϫ mice are markedly different from those observed in age- and sex-matched wild type mice, we investigated whether retinoic acid levels might be different in liver, adipose tissue, and testes of 3-month-old male LratϪ/Ϫ mice compared with male wild type mice (TABLE TWO)

  • When we provided free retinol or holo-cytosolic retinol-binding protein type III (CRBPIII), each at a final concentration of 16 ␮M, we observed for the diacylglycerol acyltransferase 1 (DGAT1)-expressing HEK293 microsomes specific activities that were respectively, 72.9 Ϯ 3.8 ng of retinyl ester formed per mg of protein/min (n ϭ 3) and 26.3 Ϯ 0.4 ng of retinyl ester formed per mg of protein/min (n ϭ 3)

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Summary

Introduction

Latory activities of retinoids are thought to result from the actions of all-trans- and 9-cis-retinoic acid (6 – 8). Most tissues possess some capacity to esterify and store retinol prior to its use for the synthesis of retinal or retinoic acid [9, 10, 14] It is generally agreed upon in the literature that retinol is esterified primarily through the actions of the enzyme lecithin:retinol acyltransferase (LRAT) [17,18,19,20]. We are interested in studying the importance of retinyl esters and LRAT in the uptake of dietary retinoid and its storage in the liver and other tissues and in understanding how retinyl ester accumulation influences normal retinoid-dependent functions in the body. We report further characterizations of the LratϪ/Ϫ mice that are relevant for understanding the role of LRAT and retinyl esters in maintaining normal retinoid-dependent function and preventing disease

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