Sirt1 coordinates with ERα to regulate autophagy and adiposity

AbstractSex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.

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Epigenetically Deregulated microRNA-375 Is Involved in a Positive Feedback Loop with Estrogen Receptor α in Breast Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-10-1318 ◽

2010 ◽

Vol 70 (22) ◽

pp. 9175-9184 ◽

Cited By ~ 197

Author(s):

Pedro de Souza Rocha Simonini ◽

Achim Breiling ◽

Nibedita Gupta ◽

Mahdi Malekpour ◽

Mahmoud Youns ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Positive Feedback ◽

Breast Cancer Cells ◽

Feedback Loop ◽

Estrogen Receptor Α ◽

Positive Feedback Loop

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P53/miR-34a/SIRT1 Positive Feedback Loop regulates cell proliferation and promotes cell apoptosis in the termination stage of liver regeneration.

10.21203/rs.3.rs-108116/v2 ◽

2021 ◽

Author(s):

Junhua Gong ◽

Minghua Cong ◽

Hao Wu ◽

Menghao Wang ◽

He Bai ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Positive Feedback ◽

Cell Apoptosis ◽

Feedback Loop ◽

Late Phase ◽

Liver Weight ◽

Positive Feedback Loop ◽

And Function ◽

Shed Light

Abstract Background The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury or cancer resection. In our study, we found that the P53/miR-34a/SIRT1 positive feedback loop has a remarkable negative regulatory effect, which is related to the termination of liver regeneration. Here, we described how P53/miR-34a/SIRT1 positive feedback loop controls liver regeneration and its possible relationship with liver cancer.Method We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) knock-downing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. Mice from the Ade-P53 group showed smaller livers and higher levels of serum ALT and AST than control mice. While knock-down of miR-34a abolished P53/miR-34a/SIRT1 positive feedback loop during LR. Mice from anti-miR-34a group showed larger livers and lower levels of PCNA-positive cells than control mice. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. Conclusion The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings shed light on the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

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T-β-MCA Regulates the Termination of Liver Regeneration via the P53/miR-34a/SIRT1 Positive Feedback Loop by Suppressing the FXR/SHP Signaling Pathway.

10.21203/rs.3.rs-108116/v1 ◽

2020 ◽

Author(s):

Fangchao Yuan ◽

Yao Chen ◽

Hao Wu ◽

Minghua Cong ◽

Menghao Wang ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Positive Feedback ◽

Feedback Loop ◽

Late Phase ◽

Liver Weight ◽

Wild Type ◽

Positive Feedback Loop ◽

And Function ◽

Shed Light

Abstract Background The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury or cancer resection. In our previous study, we initially found that the P53/miR-34a/SIRT1 positive feedback loop has a remarkable negative regulatory effect, which is related to the termination of liver regeneration. Here, we described how P53/miR-34a/SIRT1 positive feedback loop controls liver regeneration and its possible relationship with liver cancer.Method We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) knock-downing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. Mice from the Ade-P53 group showed smaller livers and higher levels of serum ALT and AST than control mice. While knock-down of miR-34a abolished P53/miR-34a/SIRT1 positive feedback loop during LR. Mice from anti-miR-34a group showed larger livers and lower levels of PCNA-positive cells than control mice. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. Conclusion The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings shed light on the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

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