(P01-006-23) Role of Mouse Carboxylesterase CES1d in the Hepatic Metabolism of Dietary Vitamin A

Objectives: Carboxylesterases (Ces) are enzymes that play roles in lipid metabolism. Genes encoding 20 mouse Ces have been defined. Four murine enzymes in the Ces1 subfamily have retinyl ester hydrolase (REH) activities. Previous studies suggest that Ces1d is a critical enzyme for the RE hydrolysis required for the uptake and storage of dietary vitamin A as well as the mobilization of hepatic RE stores. This has not been confirmed in studies using animal models. We hypothesized that Ces1d-/- mice are not able to hydrolyze REs. This will markedly impair their ability to accumulate hepatic RE when maintained on adequate dietary vitamin A. We also predicted that these animals would have impaired ability to mobilize RE stores from the liver, when placed on a vitamin A deficient diet.

Methods: All studies utilized 2-month-old mice maintained on control chow from weaning until used for dietary studies. To investigate whether Ces1d is a physiologically relevant REH, WT and KO mice were placed on either a purified nutritionally complete AIN-93G diet or the same diet but lacking any vitamin A. Total vitamin A was extracted from serum and tissues and analyzed using HPLC.

Results: Serum, lung, and liver free retinol levels were not different between Ces1d-/- and WT mice fed a purified vitamin A sufficient diet. However, we observed that liver and lung RE stores were significantly reduced in Ces1d-/- compared with WT. Indeed, the global deficiency of Ces1d resulted in 23% and 27% decreases in hepatic RE stores for female and male mice, respectively. For animals on a purified vitamin A deficient diet, there were no differences in serum, lung, and hepatic free retinol levrls in Ces1d-/- and WT mice nor were there differences in lung and liver RE stores in Ces1d-/- and WT mice.

Conclusions: The findings show that Ces1d influences the uptake and storage of dietary vitamin A in liver and lungs. These data also suggest that Ces1d is not required for the mobilization of RE stores from the liver. Hence, there are likely additional physiologically relevant hepatic REHs given the multiplicity of Ces1 isoforms. Our studies extend the fundamental understanding of the molecular mechanisms that allow the body to accumulate liver RE stores from dietary vitamin A.

Funding Sources: National Institute of Diabetes, Digestive and Kidney Diseases (NIH)