Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis
Abstract 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 exp...
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BMC
2025-05-01
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| Series: | Lipids in Health and Disease |
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| Online Access: | https://doi.org/10.1186/s12944-025-02575-w |
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| author | Le Xu Jian Xu Wanting Shi Sa Zhang Ting Guo Shien Zou |
| author_facet | Le Xu Jian Xu Wanting Shi Sa Zhang Ting Guo Shien Zou |
| author_sort | Le Xu |
| collection | DOAJ |
| description | Abstract 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 (E2) 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. |
| format | Article |
| id | doaj-art-2cd3f1b92e2c4b3fa3a5252c932c07fe |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Lipids in Health and Disease |
| spelling | doaj-art-2cd3f1b92e2c4b3fa3a5252c932c07fe2025-08-20T02:15:12ZengBMCLipids in Health and Disease1476-511X2025-05-0124111510.1186/s12944-025-02575-wDecreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesisLe Xu0Jian Xu1Wanting Shi2Sa Zhang3Ting Guo4Shien Zou5Obstetrics and Gynecology Hospital of Fudan UniversityTaian Maternity and Child Health HospitalObstetrics and Gynecology Hospital of Fudan UniversityObstetrics and Gynecology Hospital of Fudan UniversityObstetrics and Gynecology Hospital of Fudan UniversityObstetrics and Gynecology Hospital of Fudan UniversityAbstract 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 (E2) 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.https://doi.org/10.1186/s12944-025-02575-wMenopause17β-estradiolFSHCholesterol metabolism disorderPRKRA |
| spellingShingle | Le Xu Jian Xu Wanting Shi Sa Zhang Ting Guo Shien Zou Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis Lipids in Health and Disease Menopause 17β-estradiol FSH Cholesterol metabolism disorder PRKRA |
| title | Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis |
| title_full | Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis |
| title_fullStr | Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis |
| title_full_unstemmed | Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis |
| title_short | Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis |
| title_sort | decreased protein activator of interferon induced protein kinase prkra involved in menopause related cholesterol metabolic disorders by regulating cholesterol biosynthesis |
| topic | Menopause 17β-estradiol FSH Cholesterol metabolism disorder PRKRA |
| url | https://doi.org/10.1186/s12944-025-02575-w |
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