Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction
| العنوان: | Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction |
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| المؤلفون: | Joseph A. Hill, Xuliang Wang, Nan Jiang, Soo Young Kim, Stephen B. Spurgin, Hande Piristine, Sergio Lavandero, Kristin M. French, Vlad G. Zaha, Francisco Altamirano, Subhajit Dasgupta, Anwarul Ferdous, Theodore M. Hill, Herman I. May, Thomas G. Gillette, Maayan Waldman, Dan Tong, Gabriele G. Schiattarella, Heesoo Yoo, Yuxuan Luo, Elisa Villalobos |
| المساهمون: | Schiattarella, G. G., Altamirano, F., Kim, S. Y., Tong, D., Ferdous, A., Piristine, H., Dasgupta, S., Wang, X., French, K. M., Villalobos, E., Spurgin, S. B., Waldman, M., Jiang, N., May, H. I., Hill, T. M., Luo, Y., Yoo, H., Zaha, V. G., Lavandero, S., Gillette, T. G., Hill, J. A. |
| المصدر: | Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, X-Box Binding Protein 1, Ubiquitin-Protein Ligase, Transcription, Genetic, General Physics and Astronomy, FOXO1, 030204 cardiovascular system & hematology, Heart Ventricle, Mice, 0302 clinical medicine, Ubiquitin, HEK293 Cell, Myocytes, Cardiac, Proteolysi, Conserved Sequence, Multidisciplinary, biology, Chemistry, Forkhead Box Protein O1, Protein Stability, Cell biology, Ubiquitin ligase, Phenotype, Cell signalling, Human, Heart Ventricles, Ubiquitin-Protein Ligases, Science, Models, Biological, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, Transcription factor, STUB1, Heart Failure, Binding Sites, Base Sequence, Animal, Myocardium, Binding Site, Stroke Volume, General Chemistry, medicine.disease, Lipid Metabolism, Myocardial Contraction, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, Cardiovascular and Metabolic Diseases, Heart failure, Proteolysis, biology.protein, Unfolded protein response, Heart failure with preserved ejection fraction, Gene Deletion |
| الوصف: | Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes. Heart failure with preserved ejection fraction (HFpEF) is a global, major health issue for which no effective therapies are available. Here, the authors discover that the interplay between two transcription factors, Xbp1s and FoxO1, is critical for metabolic adaptation and lipid handling in HFpEF-stressed cardiomyocytes. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1b81c76663dfe090feb3e2f4b003006Test https://doaj.org/article/5e96ad72a7fc4e428e30cd13deb2825bTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a1b81c76663dfe090feb3e2f4b003006 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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