Retinoids (retinol, or vitamin A, and its metabolic derivatives) play key roles in skin and hair biology. Both deficiency of retinoids and excess retinoids severely impair skin and hair function. The highly specific requirements for retinoids in the skin underscore the importance of maintaining retinoid homeostasis for normal skin biology. Nevertheless, the factors that regulate retinoid homeostasis in the skin are incompletely understood. Our laboratory recently showed that in in vitro assays, the microsomal enzyme encoded by Dgat1, an enzyme previously established to be important for triglyceride and energy metabolism, also possesses acyl CoA:retinol acyltransferase (ARAT) activity, an enzymatic activity that covalently joins retinol with a fatty acyl-CoA moiety to form retinyl esters. The goal of this dissertation was to determine whether the enzyme encoded by Dgat1 functions as an ARAT enzyme in the skin and plays a role in maintaining retinoid homeostasis in the skin. Because mice lacking Dgat1 (Dgat1^−/− mice) exhibit prominent alopecia, a well-established toxic consequence of excess retinoic acid (RA) signaling in the skin, I hypothesized that Dgat1 functions to protect against retinoid toxicity in the skin by preventing the accumulation of unesterified retinol, which can drive excess RA biosynthesis.

First, I characterized the alopecia phenotype of Dgat1 ^−/− mice and revealed Dgat1 as a novel regulator of hair cycling. Dgat1^−/− mice exhibit altered hair cycling characterized by a prolonged first anagen phase and the precocious onset of the second anagen phase at ∼8 weeks of age. Consistent with the lack of evidence for hair cycle arrest, the alopecia of Dgat1^−/− mice does not result from an arrest in hair growth but from excessive hair shedding. Because the onset of excessive shedding at 9 weeks of age coincides with the precocious onset of the second anagen phase, the alopecia manifests as a cyclical pattern of hair loss followed by immediate hair re-growth, a pattern that persists in older animals. Analysis of Dgat1 expression in the skin during the depilation-induced hair cycle showed highest levels of Dgat1 mRNA detected during telogen. This data, together with the increased propensity of Dgat1^−/− follicles to be in anagen, suggest that Dgat1 likely plays a role in maintaining hair follicles in the quiescent telogen phase.

Next, I examined retinol metabolism in skin of Dgat1^−/− mice. I found that Dgat1 is the principal ARAT in the skin responsible for 90% of the total ARAT activity. In the absence of Dgat1, elevated levels of retinol and all-trans -RA, as well as increased RA signaling were detected in skin. The excess RA in the skin is the cause of alopecia in Dgat1^−/− mice because dietary retinol deprivation reduced skin RA levels and prevented the alopecia. Selective deletion of Dgat1 in the epidermis was sufficient to cause alopecia, indicating the retinol acyltransferase function of DGAT1 is epidermis-autonomous. Dgat1 ^−/− skin was also more susceptible to topical retinol-induced toxicity suggesting Dgat1 protects against the accumulation of unesterified retinol in the skin. From these findings, I concluded that the enzyme encoded by Dgat1 functions as a retinol acyltransferase in the epidermis where it plays a pivotal role in maintaining retinoid homeostasis, likely by restricting RA biosynthesis through controlling retinol levels. The work presented in this dissertation highlights previously unrecognized roles for DGAT1 as an ARAT enzyme in the skin and as a novel regulator of hair cycling.