Cyp27b1缺乏症通过破坏1,25(OH)2D3对脂质代谢和氧化还原稳态的调节机制，损害卵巢发育

Abstract

Female reproductive disorders are closely associated with ovarian oxidative stress and lipid dysregulation, but the upstream triggers remain poorly defined. In this study, we found that Cyp27b1, a key mitochondrial enzyme that catalyzes the conversion of 25-hydroxyvitamin D 3 (25(OH)D 3 ) to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), is an important regulator of ovarian lipid homeostasis and redox balance. In the cyp27b1 −/− zebrafish model, cyp27b1 deletion impaired ovarian development and caused mitochondrial dysfunction and oxidative stress, all of which were alleviated by exogenous 1,25(OH) 2 D 3 treatment. Lipidomic analysis revealed an abnormal accumulation of triglycerides (TG) and diglycerides (DG) in the knockout group, while phosphatidylcholine (PC) and phosphatidylethanolamine (PE), key membrane lipid components, were significantly reduced, disrupting membrane integrity and energy homeostasis. Dual-luciferase reporter assays showed that 1,25(OH) 2 D 3 increased pnpla2 promoter activity through a predicted vitamin D response element, thereby promoting TG hydrolysis in cyp27b1 −/− ovaries. In contrast, insufficient 1,25(OH) 2 D 3 production increased Pparγ expression and promoted abnormal lipid deposition. Exogenous 1,25(OH) 2 D 3 treatment reduced lipid deposition and restored Pparγ and Pnpla2 expression toward normal levels. In conclusion, our findings suggested that Cyp27b1 deficiency impaired ovarian development through lipid overload associated oxidative damage. These results linked impaired Cyp27b1 mediated 1,25(OH) 2 D 3 production to ovarian lipid metabolic disturbance and redox imbalance. Lipid metabolic changes involving pnpla2 and pparγ may represent potential regulatory targets for 1,25(OH) 2 D 3 deficiency associated ovarian pathologies. Graphical Cyp27b1 deficiency impairs ovarian development through impaired 1,25(OH) 2 D 3 production, resulting in lipid dysregulation, redox imbalance, mitochondrial dysfunction, and oxidative stress. 1,25(