Le Xu, Jian Xu, Wanting Shi, Sa Zhang, Ting Guo, Shien Zou
{"title":"干扰素诱导蛋白激酶（PRKRA）蛋白激活因子的降低通过调节胆固醇生物合成参与绝经相关胆固醇代谢紊乱。","authors":"Le Xu, Jian Xu, Wanting Shi, Sa Zhang, Ting Guo, Shien Zou","doi":"10.1186/s12944-025-02575-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The ovariectomized mouse model exhibited abnormal lipid profiles that correlated with reduced PRKRA expression in the liver. In vitro, 17β-estradiol (E<sub>2</sub>) 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":18073,"journal":{"name":"Lipids in Health and Disease","volume":"24 1","pages":"171"},"PeriodicalIF":3.9000,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065379/pdf/","citationCount":"0","resultStr":"{\"title\":\"Decreased protein activator of interferon induced protein kinase (PRKRA) involved in menopause-related cholesterol metabolic disorders by regulating cholesterol biosynthesis.\",\"authors\":\"Le Xu, Jian Xu, Wanting Shi, Sa Zhang, Ting Guo, Shien Zou\",\"doi\":\"10.1186/s12944-025-02575-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The ovariectomized mouse model exhibited abnormal lipid profiles that correlated with reduced PRKRA expression in the liver. In vitro, 17β-estradiol (E<sub>2</sub>) 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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":18073,\"journal\":{\"name\":\"Lipids in Health and Disease\",\"volume\":\"24 1\",\"pages\":\"171\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-05-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065379/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Lipids in Health and Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12944-025-02575-w\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lipids in Health and Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12944-025-02575-w","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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 (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.
期刊介绍：
Lipids in Health and Disease is an open access, peer-reviewed, journal that publishes articles on all aspects of lipids: their biochemistry, pharmacology, toxicology, role in health and disease, and the synthesis of new lipid compounds.
Lipids in Health and Disease is aimed at all scientists, health professionals and physicians interested in the area of lipids. Lipids are defined here in their broadest sense, to include: cholesterol, essential fatty acids, saturated fatty acids, phospholipids, inositol lipids, second messenger lipids, enzymes and synthetic machinery that is involved in the metabolism of various lipids in the cells and tissues, and also various aspects of lipid transport, etc. In addition, the journal also publishes research that investigates and defines the role of lipids in various physiological processes, pathology and disease. In particular, the journal aims to bridge the gap between the bench and the clinic by publishing articles that are particularly relevant to human diseases and the role of lipids in the management of various diseases.
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