UCSF

The requirement for retinoic acid (RA) signaling in the skin is highly specific. Abnormally elevated RA in the skin is a well-known cause of alopecia. We demonstrate here that a protective mechanism against excessive RA involves the esterification of retinol with a fatty acyl CoA moiety by a retinol acyltransferase enzyme, ARAT, encoded by Dgat1. We show that Dgat1 encodes the principal ARAT in murine skin where it accounts for 90% of total ARAT activity. The absence of Dgat1 resulted in abnormally elevated retinol and RA levels in the skin, and cyclical alopecia due to excessive hair shedding which was preventable by reducing retinol levels in the skin using dietary retinol deprivation. Dgat1^-/- skin also exhibited increased susceptibility to toxicity from topically applied retinol. Selective deletion of Dgat1 in the epidermis was sufficient to cause alopecia, indicating that the retinoid-related functions of Dgat1 are epidermis-autonomous. We conclude that the enzyme encoded by Dgat1 functions as a retinol acyltransferase in the epidermis, where it protects against retinoid toxicity likely by preventing the accumulation of retinol which can drive RA biosynthesis.