The long-term goals of this project are to characterize the biosynthesis of 9-cis-retinoic acid at the nutritional, biochemical and molecular levels. 9-cis-Retinoic acid is an endogenous vitamin A metabolite that activates the retinoid X receptors (RXRs). The three distinct RXRs (alpha, beta, gamma) comprise a sub-family of the steroid hormone superfamily of receptors. RXRs expedite growth and development by modulating the expression of genes with RXR response elements and by heterodimerizing with other receptors in the superfamily, including the all-trans-retinoic acid receptors, RARs. We have generated data indicating that a rat liver cytosolic 9-cis-retinol dehydrogenase catalyzes the conversion of 9-cis-retinol into 9-cis-retinal. This step is distinct from the first reaction in the path of all-trans-retinoic acid biosynthesis, which relies on a microsomal all-trans-retinol dehydrogenase. From these and other data, we hypothesize that 9-cis- retinoic acid would be biosynthesized independently of all-trans-retinoic acid; i.e. all-trans-retinoic acid would not be an obligatory intermediate in 9-cis-retinoic acid synthesis.
The Specific Aims are to: 1) determine the major pathway of 9-cis-retinoic acid biosynthesis; 2) determine whether 9-cis-retinol and 9-cis-retinoic acid are converted into their respective all-trans-isomers in vivo; 3) determine whether a binding protein specific for 9-cis-retinol exists; 4) characterize enzymes that catalyze the isomerization of all-trans- into 9-cis- retinoids and the dehydrogenation of 9-cis-retinol into 9-cis-retinal, including whether these enzymes are regulated by 9-cis- or all-trans- retinoids in vitro; 5) determine whether 9-cis-retinoic acid or all- trans-retinoic acid administered in vivo to vitamin A-deficient rats modulate enzymes specific to 9-cis-retinoic acid biosynthesis. This work would not only establish the route or routes of 9-cis-retinoic acid synthesis, it would help determine whether there are nutritional or biochemical interactions between the synthesis of 9-cis- and all-trans- retinoic acids, and provide initial insight into how dietary 9-cis- retinoids might impact on retinoid functions/metabolism.
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