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J. Biol. Chem., Vol. 280, Issue 30, 27815-27825, July 29, 2005

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Metabolism and Transactivation Activity of 13,14-Dihydroretinoic Acid^*

Alexander R. Moise, Vladimir Kuksa, William S. Blaner, Wolfgang Baehr¶||**, and Krzysztof Palczewski¶¶

From the Departments of Ophthalmology, Pharmacology, and Chemistry, University of Washington, Seattle, Washington 98195, the ^¶Departments of Ophthalmology and Visual Sciences, ^||Biology, and ^**Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84112, and the Department of Medicine and Institute of Human Nutrition, Columbia University, New York, New York 10032

The metabolism of vitamin A is a highly regulated process that generates essential mediators involved in the development, cellular differentiation, immunity, and vision of vertebrates. Retinol saturase converts all-trans-retinol to all-trans-13,14-dihydroretinol (Moise, A. R., Kuksa, V., Imanishi, Y., and Palczewski, K. (2004) J. Biol. Chem. 279, 50230–50242). Here we demonstrate that the enzymes involved in oxidation of retinol to retinoic acid and then to oxidized retinoic acid metabolites are also involved in the synthesis and oxidation of all-trans-13,14-dihydroretinoic acid. All-trans-13,14-dihydroretinoic acid can activate retinoic acid receptor/retinoid X receptor heterodimers but not retinoid X receptor homodimers in reporter cell assays. All-trans-13,14-dihydroretinoic acid was detected in vivo in Lrat-/- mice supplemented with retinyl palmitate. Thus, all-trans-13,14-dihydroretinoic acid is a naturally occurring retinoid and a potential ligand for nuclear receptors. This new metabolite can also be an intermediate in a retinol degradation pathway or it can serve as a precursor for the synthesis of bioactive 13,14-dihydroretinoid metabolites.

Received for publication, March 31, 2005 , and in revised form, May 18, 2005.

^* This work was supported by National Institutes of Health Grants EY08061 and EY08123, a grant from the Macular Vision Research Foundation, and a grant from the E. K. Bishop Foundation. 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 Table II and Figs. 7–10.

^¶¶ To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Box 356485, Seattle, WA 98195-6485. Tel.: 206-543-9074; Fax: 206-221-6784; E-mail: palczews{at}u.washington.edu.

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