Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis.

BACKGROUND: Menopause-related cholesterol metabolic disorders pose a global health concern, but the underlying mechanism is unclear. PRKRA was identified as a potential regulator of cholesterol metabolism in an exome-wide association study. Our prior research revealed a decrease in PRKRA expression in the ovarian cortex of postmenopausal women. However, its involvement in cholesterol metabolism disturbances in postmenopausal females remains unclear. This study aimed to investigate the association between PRKRA and cholesterol metabolism disorders in ovariectomized mice. Additionally, we elucidated the impact and underlying mechanisms of PRKRA on cholesterol metabolism in HepG2 and HuH7 cells. METHODS: An ovariectomized mouse model was generated, and the mice were fed a standard diet for six months to simulate menopausal conditions. PRKRA expression in mouse liver tissue was evaluated by qPCR and western blotting. Spearman correlation analysis was used to explore the relationship between the PRKRA mRNA level and the serum total cholesterol concentration. In vitro, we investigated the influence of PRKRA on cholesterol levels and Dil-LDL uptake capacity in HepG2 and HuH7 cells. Additionally, transcriptome sequencing was employed to analyze the intrinsic mechanisms involved. RESULTS: The ovariectomized mouse model exhibited abnormal lipid profiles that correlated with reduced PRKRA expression in the liver. In vitro, 17β-estradiol (E(2)) upregulated PRKRA expression, while follicle-stimulating hormone (FSH) downregulated it in HepG2 and HuH7 cells. PRKRA knockdown increased intracellular total cholesterol and decreased Dil-LDL uptake, while PRKRA overexpression had the opposite effects. Mechanistically, reduced PRKRA levels were associated with HMGCS1 upregulation and LDLR downregulation. CONCLUSION: Ovariectomy for six months independently induced an aberrant cholesterol phenotype in mice. Downregulation of PRKRA was implicated in cholesterol metabolism disturbances related to menopause, potentially through the regulation of cholesterol synthesis and LDL uptake.