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J. Biol. Chem., Vol. 283, Issue 20, 13510-13519, May 16, 2008

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The Molecular Basis of Retinoid Absorption

A Genetic Dissection^*

Nuttaporn Wongsiriroj, Roseann Piantedosi, Krzysztof Palczewski, Ira J. Goldberg, Thomas P. Johnston^¶, Ellen Li^||, and William S. Blaner¹

From the Institute of Human Nutrition and Department of Medicine, Columbia University, New York, New York 10032, the Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, ^¶School of Pharmacy, University of Missouri, Kansas City, Missouri 64110, and the ^||Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

The intestine and other tissues are able to synthesize retinyl esters in an acyl-CoA-dependent manner involving an acyl-CoA:retinol acyltransferase (ARAT). However, the molecular identity of this ARAT has not been established. Recent studies of lecithin:retinol acyltransferase (LRAT)-deficient mice indicate that LRAT is responsible for the preponderance of retinyl ester synthesis in the body, aside from in the intestine and adipose tissue. Our present studies, employing a number of mutant mouse models, identify diacylglycerol acyltransferase 1 (DGAT1) as an important intestinal ARAT in vivo. The contribution that DGAT1 makes to intestinal retinyl ester synthesis becomes greater when a large pharmacologic dose of retinol is administered by gavage to mice. Moreover, when large retinol doses are administered another intestinal enzyme(s) with ARAT activity becomes apparent. Surprisingly, although DGAT1 is expressed in adipose tissue, DGAT1 does not catalyze retinyl ester synthesis in adipose tissue in vivo. Our data also establish that cellular retinol-binding protein, type II (CRBPII), which is expressed solely in the adult intestine, in vivo channels retinol to LRAT for retinyl ester synthesis. Contrary to what has been proposed in the literature based on in vitro studies, CRBPII does not directly prevent retinol from being acted upon by DGAT1 or other intestinal ARATs in vivo.

Received for publication, January 30, 2008 , and in revised form, March 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK061310, R01 DK068437, R01 DK079221, R01 EY08123, R01 EY09339, and P30 DK052574. 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 To whom correspondence should be addressed: Black Bldg., Rm. 914, Dept. of Medicine, Columbia University, 650 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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