Absence of Vitamin D Receptor-Mediated PPARγ Suppression Causes Alopecia in VDR-Null Mice

The study investigated the role of the vitamin D receptor (VDR) in hair loss by examining VDR-null (VDR−/−) mice, which exhibited alopecia due to impaired keratinocyte stem cell (KSC) function. RNA sequencing revealed that over 80% of differentially expressed genes were up-regulated in VDR−/− KSCs, indicating that VDR acts as a transcriptional suppressor in wild-type KSCs. Key up-regulated genes included PPARγ, PGC1β, and LPL, which are direct VDR targets. The absence of VDR allowed PPARγ to occupy its regulatory region, unlike in wild-type keratinocytes. Mice with keratinocyte-specific PPARγ haploinsufficiency showed normalized PPARγ mRNA levels and restored hair growth, suggesting that the lack of VDR-mediated PPARγ suppression was responsible for alopecia in VDR−/− mice.