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J. Biol. Chem., Vol. 280, Issue 42, 35647-35657, October 21, 2005

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Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT)^*

Sheila M. O'Byrne, Nuttaporn Wongsiriroj, Jenny Libien¶, Silke Vogel, Ira J. Goldberg, Wolfgang Baehr||, Krzysztof Palczewski**1, and William S. Blaner2

From the Institute of Human Nutrition and Departments of ^¶Pathology and Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, the ^||Department of Ophthalmology, the University of Utah Health Sciences Center, Salt Lake City, Utah 84112, and the ^**Departments of Ophthalmology, Pharmacology and Chemistry, the University of Washington, Seattle, Washington 98185

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.

Received for publication, July 20, 2005 , and in revised form, August 17, 2005.

^* This work was supported by National Institutes of Health Grants R01 DK061310, R01 DK068437, R01 DK067512, R01 EY08123, and R01 EY09339, United States Department of Defense Grant BC031116, and a Foundation Fighting Blindness grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Pharmacology, Case Western University School of Medicine, Cleveland, OH 44106-4965.

² To whom correspondence should be addressed: Dept. of Medicine, Columbia University, 701 W. 168th St., New York, NY 10032. Tel.: 212-305-5429; Fax: 212-305-2801; E-mail: wsb2{at}columbia.edu.

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