807 Homocysteine induces apoptosis of melanocytes via PERK-eif2α-CHOP pathway in vitiligo

Abstract

Hyperhomocysteinemia and folic acid deficiencies have been reported in patients with vitligo, while the mechanism underlying this process is unclear. This study aims to investigate the effect of homocysteine (Hcy) on vitiligo pathogenesis and the underlying mechanisms. Our results demonstrated that Hcy was highly expressed in the serum of patients with vitiligo and associated with the degree of disease progression. In vitro study confirmed that oxidative stress can promote the accumulation of Hcy in melanocytes. Hcy treatment can inhibit melanocyte growth and induce cell apoptosis in a dose-dependent manner. Hcy treatment can upregulate glucose-regulated protein 78(GRP78), activate endoplasmic reticulum stress and induce the expression of C/EBP homologous protein(CHOP). Knockout the IRE1 pathway has no effect on apoptosis, whereas, the level of apoptosis is reduced by knockout the PERK pathway. We also observed activation of pPERK in peripheral melanocytes of vitiligo patient. Folic acid serves as cofactors of homocysteine methyltransferase of methionine from homocysteine. Folic acid supplementation can reduce intracellular Hcy levels, inhibit the activation of the perk-eif2a-CHOP pathway, reduce cell apoptosis rate and promote melanocyte surivival. Our study also showed that homosysteine disrupts melanogenesis via inhibition of MITF TYR TYRP1 and melanA experssion, supplementation of folic acid can restore above molecular expression and restore melanin synthesis. Our data suggest that an elevated Hcy level may be a precipitating factor for vitiligo in predisposed individuals. In addition, Hcy facilitate melanocyte apoptosis through perk-eif2a-CHOP pathway, and decrease melanin synthesis. Importantly, folic acid supplementation can reduce the Hcy toxicity to melanocyte and restore melanin synthesis.