Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways
Background. Testosterone deficiency is reportedly correlated with an elevation of cholesterol in plasma, but the mechanism remains unclear. Our objective was to investigate the effects of testosterone deficiency on cholesterol metabolism and the corresponding molecular changes in vivo and in vitro....
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| Format: | Article |
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Wiley
2022-01-01
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| Series: | International Journal of Endocrinology |
| Online Access: | http://dx.doi.org/10.1155/2022/7989751 |
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| author | Yu Yuefeng Lin Zhiqi Chen Yi Zhu Keyu Wan Heng Wang Yuying Wang Ningjian Yu Yuetian Gu Xinjie Zhang Yihao Lu Yingli Xia Fangzhen |
| author_facet | Yu Yuefeng Lin Zhiqi Chen Yi Zhu Keyu Wan Heng Wang Yuying Wang Ningjian Yu Yuetian Gu Xinjie Zhang Yihao Lu Yingli Xia Fangzhen |
| author_sort | Yu Yuefeng |
| collection | DOAJ |
| description | Background. Testosterone deficiency is reportedly correlated with an elevation of cholesterol in plasma, but the mechanism remains unclear. Our objective was to investigate the effects of testosterone deficiency on cholesterol metabolism and the corresponding molecular changes in vivo and in vitro. Methods. SD rats were randomized into three groups: sham-operated (SHAM), subtotal orchiectomized (SO), and orchiectomized (ORX) and fed for 8 weeks. HepG2 cells were cultured with medium containing testosterone with the final concentrations of 0, 10, 30, and 300 nM. Method of isotope tracing and fluorescence labelling was adopted to investigate cholesterol metabolism. Several key molecules of cholesterol metabolism were also analyzed. Results. SO and ORX rats displayed dysfunctional liver uptake of cholesterol. HepG2 cells incubated with testosterone of lower and excessive level exhibited reduced capacity of cholesterol uptake. Further investigation revealed that lack of testosterone induced increased proprotein convertase subtilisin/kexin type 9 (PCSK9) and decreased low-density lipoprotein receptor (LDLR) both in vivo and in vitro. Moreover, the androgen receptor (AR) antagonist flutamide mimicked the effects of testosterone deficiency on PCSK9 and LDLR indicating the role of AR as a mediator in triggering attenuating liver cholesterol uptake in which testosterone instead of dihydrotestosterone (DHT) is the major functional form of androgen. Conclusion. Testosterone deficiency attenuated cholesterol liver uptake mediated by the PCSK9-LDLR pathway, in which AR and testosterone without transforming to DHT play important roles. |
| format | Article |
| id | doaj-art-1444cefb3b1f48c2a7db957d64081f4f |
| institution | OA Journals |
| issn | 1687-8345 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Endocrinology |
| spelling | doaj-art-1444cefb3b1f48c2a7db957d64081f4f2025-08-20T02:04:52ZengWileyInternational Journal of Endocrinology1687-83452022-01-01202210.1155/2022/7989751Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR PathwaysYu Yuefeng0Lin Zhiqi1Chen Yi2Zhu Keyu3Wan Heng4Wang Yuying5Wang Ningjian6Yu Yuetian7Gu Xinjie8Zhang Yihao9Lu Yingli10Xia Fangzhen11Institute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismInstitute and Department of Endocrinology and MetabolismBackground. Testosterone deficiency is reportedly correlated with an elevation of cholesterol in plasma, but the mechanism remains unclear. Our objective was to investigate the effects of testosterone deficiency on cholesterol metabolism and the corresponding molecular changes in vivo and in vitro. Methods. SD rats were randomized into three groups: sham-operated (SHAM), subtotal orchiectomized (SO), and orchiectomized (ORX) and fed for 8 weeks. HepG2 cells were cultured with medium containing testosterone with the final concentrations of 0, 10, 30, and 300 nM. Method of isotope tracing and fluorescence labelling was adopted to investigate cholesterol metabolism. Several key molecules of cholesterol metabolism were also analyzed. Results. SO and ORX rats displayed dysfunctional liver uptake of cholesterol. HepG2 cells incubated with testosterone of lower and excessive level exhibited reduced capacity of cholesterol uptake. Further investigation revealed that lack of testosterone induced increased proprotein convertase subtilisin/kexin type 9 (PCSK9) and decreased low-density lipoprotein receptor (LDLR) both in vivo and in vitro. Moreover, the androgen receptor (AR) antagonist flutamide mimicked the effects of testosterone deficiency on PCSK9 and LDLR indicating the role of AR as a mediator in triggering attenuating liver cholesterol uptake in which testosterone instead of dihydrotestosterone (DHT) is the major functional form of androgen. Conclusion. Testosterone deficiency attenuated cholesterol liver uptake mediated by the PCSK9-LDLR pathway, in which AR and testosterone without transforming to DHT play important roles.http://dx.doi.org/10.1155/2022/7989751 |
| spellingShingle | Yu Yuefeng Lin Zhiqi Chen Yi Zhu Keyu Wan Heng Wang Yuying Wang Ningjian Yu Yuetian Gu Xinjie Zhang Yihao Lu Yingli Xia Fangzhen Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways International Journal of Endocrinology |
| title | Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways |
| title_full | Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways |
| title_fullStr | Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways |
| title_full_unstemmed | Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways |
| title_short | Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR Pathways |
| title_sort | testosterone deficiency promotes hypercholesteremia and attenuates cholesterol liver uptake via ar pcsk9 ldlr pathways |
| url | http://dx.doi.org/10.1155/2022/7989751 |
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