Vitamin D regulates lipid metabolism in granulosa cells via the FABP3-associated PI3K/Akt pathway in polycystic ovary syndrome.

OBJECTIVES

To investigate whether vitamin D (VD) affects lipid metabolism in granulosa cells in polycystic ovary syndrome (PCOS) through the FABP3-associated PI3K/Akt pathway.

METHODS

PCOS rat models were established using letrozole, followed by ovarian transcriptome sequencing, which revealed significant enrichment of lipid metabolism- and PI3K/Akt signaling-related pathways and identified FABP3 as a candidate gene for further investigation. Dehydroepiandrosterone (DHEA)-treated KGN cells were used as a PCOS cell model. FABP3 knockdown/overexpression, VD treatment, and PI3K/Akt inhibition were used to investigate the FABP3-associated PI3K/Akt pathway. Lipid metabolism-related regulators, including FABP3, FASN, ATGL, PPARγ, p-PI3K, and p-Akt, as well as cell viability and proliferation, free fatty acid (FFA) levels, and perilipin-2 expression, were evaluated. In vivo validation in VD-treated PCOS rats and ovarian tissue metabolomics were also performed.

RESULTS

Immunohistochemical analysis revealed increased FABP3 and perilipin-2 immunoreactivity in ovarian tissues from PCOS rats. In DHEA-treated KGN cells, DHEA upregulated FABP3, FASN, and PPARγ, downregulated ATGL, inhibited PI3K/Akt phosphorylation, elevated FFA levels and perilipin-2 expression, and reduced cell viability and proliferation. Knockdown of FABP3 largely reversed these DHEA-induced alterations. Similarly, VD treatment alleviated DHEA-induced fatty acid metabolic disorders by decreasing FABP3, FASN, and PPARγ expression, increasing ATGL expression and PI3K/Akt phosphorylation, reducing FFA levels and perilipin-2 expression, and enhancing KGN cell viability and proliferation. The protective effects of VD were abolished by FABP3 overexpression or PI3K/Akt inhibition. In vivo, VD markedly attenuated polycystic ovarian changes and reduced FABP3 and perilipin-2 immunoreactivity in PCOS rats, accompanied by decreased FABP3, FASN, and PPARγ expression and increased ATGL expression and PI3K/Akt phosphorylation in ovarian tissues. Ovarian tissue metabolomics further demonstrated that VD significantly altered lipid metabolite profiles in PCOS.

CONCLUSIONS

VD ameliorates lipid metabolic dysregulation in PCOS by modulating the FABP3-associated PI3K/Akt pathway, thereby alleviating granulosa cell dysfunction and ovarian pathological changes.