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J. Biol. Chem., Vol. 283, Issue 9, 5611-5621, February 29, 2008

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

Youn-Kyung Kim¹, Lesley Wassef¹, Leora Hamberger, Roseann Piantedosi, Krzysztof Palczewski^¶2, William S. Blaner³, and Loredana Quadro⁴

From the Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, the Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and the ^¶Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids (vitamin A and its metabolites). The mechanisms through which mammalian developing tissues maintain adequate retinoid levels in the face of suboptimal or excessive maternal dietary vitamin A intake have not been established. We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis. Dams lacking both LRAT and retinol-binding protein (RBP), the sole specific carrier for retinol in serum, were maintained on diets containing different amounts of vitamin A during pregnancy. We hypothesized that the lack of both proteins would make the embryo more vulnerable to changes in maternal dietary vitamin A intake. Our data demonstrate that maternal dietary vitamin A deprivation during pregnancy generates a severe retinoid-deficient phenotype of the embryo due to the severe retinoid-deficient status of the double mutant dams rather than to the lack of LRAT in the developing tissues. Moreover, in the case of excessive maternal dietary vitamin A intake, LRAT acts together with Cyp26A1, one of the enzymes that catalyze the degradation of retinoic acid, and possibly with STRA6, the recently identified cell surface receptor for retinol-RBP, in maintaining adequate levels of retinoids in embryonic and extraembryonic tissues. In contrast, the pathway of retinoic acid synthesis does not contribute significantly to regulating retinoid homeostasis during mammalian development except under conditions of severe maternal retinoid deficiency.

Received for publication, October 29, 2007 , and in revised form, December 18, 2007.

^* This work was supported in part by National Research Initiative Grant 2006-35200-16580 from the U. S. Department of Agriculture Cooperative State Research, Education, and Extension Service, Bioactive Food Components for Optimal Health (31.0) Program (to L. Q.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1.

¹ Both authors contributed equally to this work.

² Supported by Grant EY09339 from the National Institutes of Health (NIH).

³ Supported by NIH Grants DK061310, DK068437, and DK079221.

⁴ To whom correspondence should be addressed: Dept. of Food Science and Rutgers Center for Lipid Research, Rutgers University, 65 Dudley Rd., New Brunswick, NJ 08901. Tel.: 732-932-9611; Fax: 732-932-6776; E-mail: quadro{at}aesop.rutgers.edu.

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