Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD
<b>Background/Objectives:</b> Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with cardiometabolic risk. Although studies have shown that estradiol positively contributes to energy metabolism via estrogen receptor alpha (ERα), its role specifically in the l...
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MDPI AG
2025-01-01
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| author | Ester S. Alves Jessica D. M. Santos Alessandra G. Cruz Felipe N. Camargo Carlos H. Z. Talarico Anne R. M. Santos Carlos A. A. Silva Henrique J. N. Morgan Sandro L. Matos Layanne C. C. Araujo João Paulo Camporez |
| author_facet | Ester S. Alves Jessica D. M. Santos Alessandra G. Cruz Felipe N. Camargo Carlos H. Z. Talarico Anne R. M. Santos Carlos A. A. Silva Henrique J. N. Morgan Sandro L. Matos Layanne C. C. Araujo João Paulo Camporez |
| author_sort | Ester S. Alves |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with cardiometabolic risk. Although studies have shown that estradiol positively contributes to energy metabolism via estrogen receptor alpha (ERα), its role specifically in the liver is not defined. Therefore, this study aimed to evaluate the effects of ERα overexpression, specifically in the liver in mice fed a high-fat diet (HFD). <b>Methods:</b> Male C57BL/6J mice were divided into four groups, vehicle fed with regular chow (RC) (RC-Vehicle); vehicle fed an HFD (HFD-Vehicle); AAV-treated fed with RC (RC-AAV); and AAV-treated fed an HFD (HFD-AAV), for 6 weeks (8–10 mice per group). AAV was administered intravenously to induce ERα overexpression. <b>Results:</b> We demonstrate that overexpression of ERα in RC-fed mice reduces body fat (28%). These mice show increased oxygen consumption in cultured primary hepatocytes, both in basal (19%) and maximal respiration (34%). In HFD-fed mice, we showed a decrease in hepatic TAG content (43%) associated with improved hepatic insulin sensitivity (145%). <b>Conclusions:</b> From this perspective, our results prove that hepatic ERα signaling is responsible for some of the metabolic protective effects of estrogen in mice. Overexpression of ERα improves hepatocyte mitochondrial function, consequently reducing hepatic lipid accumulation and protecting animals from hepatic steatosis and hepatic insulin resistance. Further investigations will be needed to determine the exact molecular mechanism by which ERα improves hepatic metabolic health. |
| format | Article |
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| institution | Kabale University |
| issn | 1873-149X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathophysiology |
| spelling | doaj-art-df2be53dc5f24c1ca94fa05248197f062025-08-20T03:43:20ZengMDPI AGPathophysiology1873-149X2025-01-01321110.3390/pathophysiology32010001Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLDEster S. Alves0Jessica D. M. Santos1Alessandra G. Cruz2Felipe N. Camargo3Carlos H. Z. Talarico4Anne R. M. Santos5Carlos A. A. Silva6Henrique J. N. Morgan7Sandro L. Matos8Layanne C. C. Araujo9João Paulo Camporez10Department of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, BrazilSuperior Institute of Biomedical Sciences, State University of Ceara, Fortaleza 60714-903, BrazilDepartment of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, Brazil<b>Background/Objectives:</b> Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with cardiometabolic risk. Although studies have shown that estradiol positively contributes to energy metabolism via estrogen receptor alpha (ERα), its role specifically in the liver is not defined. Therefore, this study aimed to evaluate the effects of ERα overexpression, specifically in the liver in mice fed a high-fat diet (HFD). <b>Methods:</b> Male C57BL/6J mice were divided into four groups, vehicle fed with regular chow (RC) (RC-Vehicle); vehicle fed an HFD (HFD-Vehicle); AAV-treated fed with RC (RC-AAV); and AAV-treated fed an HFD (HFD-AAV), for 6 weeks (8–10 mice per group). AAV was administered intravenously to induce ERα overexpression. <b>Results:</b> We demonstrate that overexpression of ERα in RC-fed mice reduces body fat (28%). These mice show increased oxygen consumption in cultured primary hepatocytes, both in basal (19%) and maximal respiration (34%). In HFD-fed mice, we showed a decrease in hepatic TAG content (43%) associated with improved hepatic insulin sensitivity (145%). <b>Conclusions:</b> From this perspective, our results prove that hepatic ERα signaling is responsible for some of the metabolic protective effects of estrogen in mice. Overexpression of ERα improves hepatocyte mitochondrial function, consequently reducing hepatic lipid accumulation and protecting animals from hepatic steatosis and hepatic insulin resistance. Further investigations will be needed to determine the exact molecular mechanism by which ERα improves hepatic metabolic health.https://www.mdpi.com/1873-149X/32/1/1insulin actionestrogen signalinghepatic insulin resistanceMASLD |
| spellingShingle | Ester S. Alves Jessica D. M. Santos Alessandra G. Cruz Felipe N. Camargo Carlos H. Z. Talarico Anne R. M. Santos Carlos A. A. Silva Henrique J. N. Morgan Sandro L. Matos Layanne C. C. Araujo João Paulo Camporez Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD Pathophysiology insulin action estrogen signaling hepatic insulin resistance MASLD |
| title | Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD |
| title_full | Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD |
| title_fullStr | Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD |
| title_full_unstemmed | Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD |
| title_short | Hepatic Estrogen Receptor Alpha Overexpression Protects Against Hepatic Insulin Resistance and MASLD |
| title_sort | hepatic estrogen receptor alpha overexpression protects against hepatic insulin resistance and masld |
| topic | insulin action estrogen signaling hepatic insulin resistance MASLD |
| url | https://www.mdpi.com/1873-149X/32/1/1 |
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