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Retinoic Acid Regulates Retinol Metabolism via Feedback Inhibition of Retinol Oxidation and Stimulation of Retinol Esterification in Ferret Liver^{1, 2,}

Xiang-Dong Wang^*,, Norman I. Krinsky and Robert M. Russell^*,3

^* Gastrointestinal Nutrition Laboratory, USDA Human Nutrition Research Center, School of Nutrition Department of Biochemistry, School of Medicine, Tufts University, Boston, MA 02111

When the plasma concentration of retinoic acid is increased, there is an accompanying reduction of circulating levels of retinol, suggesting that retinoic acid may have a regulatory effect on retinol metabolism in vivo. To determine which specific step(s) of retinol metabolism might be regulated by retinoic acid, retinol was incubated with ferret liver microsomes or cytosol with retinoic acid in vitro. Incubating the microsomal fraction with retinoic acid resulted in a dose-dependent (up to 0.5 µmol/L) decrease in the formation of retinal. On the contrary, no retinoic acid inhibitory effect was observed on retinal synthesis in the cytosol incubation, or in the cytosol plus microsome incubation. However, when retinoic acid was added to the cytosolic incubation mixture in the presence of the retinal oxidative inhibitor, citral, a dose-dependent inhibition of retinal synthesis was observed. Furthermore, the effect of retinoic acid on retinyl ester metabolism in ferret liver was studied by using endogenous retinyl esters of ferret liver as the substrate. When retinoic acid was added to the incubation mixture of microsomes plus cytosol, small, nonsignificant increases in retinol and retinyl esters were observed. When retinoic acid was added in the presence of citral, both the inhibition of retinol oxidation and the stimulation of retinol esterification were dose dependent up to 0.3 µmol/L and then remained the same up to 1.0 µmol/L. These data strongly suggest that retinoic acid has a regulatory effect on retinol metabolism in ferret liver, which may occur via feedback inhibition of retinol oxidation and stimulation of retinol esterification.

KEY WORDS: • retinoids • regulation • liver microsomes • liver cytosol • ferrets

¹ Funded in part by federal funds from the U.S. Department of Agriculture, Agricultural Research Service under contract no. 53-3K06-01 and by grant R01CA49195-01 from the National Institutes of Health, Bethesda, MD. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products or organizations imply endorsement by the United States government.

² 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 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 17 November 1992. Revision accepted 10 March 1993.

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