Retinol Esterification by DGAT1 Is Essential for Retinoid Homeostasis in Murine Skin

Michelle Y.S Shih,Maureen A Kane,Ping Zhou,C L Eric Yen,Ryan S Streeper,Joseph L Napoli,Robert V Farese

doi:10.1074/jbc.m807503200

Abstract

Retinoic acid (RA) is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. The synthesis of RA from its precursor retinol (vitamin A) is an important regulatory mechanism. Therefore, the esterification of retinol with fatty acyl moieties to generate retinyl esters, the main storage form of retinol, may also regulate RA levels. Here we show that the neutral lipid synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) functions as the major acyl-CoA:retinol acyltransferase (ARAT) in murine skin. When dietary retinol is abundant, DGAT1 deficiency results in elevated levels of RA in skin and cyclical hair loss; both are prevented by dietary retinol deprivation. Further, DGAT1-deficient skin exhibits enhanced sensitivity to topically administered retinol. Deletion of the enzyme specifically in the epidermis causes alopecia, indicating that the regulation of RA homeostasis by DGAT1 is autonomous in the epidermis. These findings show that DGAT1 functions as an ARAT in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity. Our findings may have implications for human skin or hair disorders treated with agents that modulate RA signaling.

Highlights

Excess Retinoic acid (RA) is highly teratogenic during embryonic development and may be toxic to adult tissues [3]
Altered Retinoid Metabolism in Dgat1Ϫ/Ϫ Skin—To determine if DGAT1 contributes to retinol esterification in skin, we measured acyl CoA:retinol acyltransferase (ARAT) activity in whole skin homogenates of 7-weekold wild-type and Dgat1Ϫ/Ϫ mice fed a chow diet
To determine if the reduced ARAT activity in Dgat1Ϫ/Ϫ skin altered retinoid homeostasis, we measured retinoid levels in whole skin of wild-type and Dgat1Ϫ/Ϫ mice fed a formulated, purified diet containing the amount of retinol recommended by the American Institute of Nutrition

Summary

Introduction

Excess RA is highly teratogenic during embryonic development and may be toxic to adult tissues [3]. Several tissues of Dgat1Ϫ/Ϫ mice had reduced ARAT activity, and retinol esterification was reduced in cultured murine embryonic fibroblasts lacking DGAT1 [14]. Altered Retinoid Metabolism in Dgat1Ϫ/Ϫ Skin—To determine if DGAT1 contributes to retinol esterification in skin, we measured ARAT activity in whole skin homogenates of 7-weekold wild-type and Dgat1Ϫ/Ϫ mice fed a chow diet.

Results

Conclusion