The protective effects of TGR5 against ultraviolet B irradiation in epidermal stem cells.

Repetitive exposure to ultraviolet radiation (UVR) results in continuous insults to the skin, including continuous loss of the capacities of epidermal stem cells (ESCs). Takeda G-protein-coupled receptor-5 (TGR5) participates in a variety of physiological activities, but its biological function in skin has not been reported. In this study, we report that TGR5 could be detected in ESCs and its expression was reduced after ultraviolet B (UV-B) irradiation. Treatment with the specific TGR5 agonist 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide (GPBARA) prevented UV-B-induced oxidative stress by reducing 4-hydroxy-2-nonenal and increasing the level of glutathione. We also found that the presence of GPBARA improved UV-B irradiation-induced mitochondrial dysfunction by elevating mitochondrial membrane potential. Interestingly, our results indicate that GPBARA pretreatment suppressed UV-B irradiation-induced reduced cell viability, release of lactic dehydrogenase, and secretion of high mobility group box 1. Notably, GPBARA pretreatment inhibited UV-B irradiation-induced decrease in integrin β1 and Krt19, dependent on TGR5. Mechanistically, we found that the activation of TGR5 by GPBARA increased Wnt1, Wnt3a, Myc, and cyclin D1 in ESCs. Our data suggest a new function of TGR5 in regulating ESCs.