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| Item Type: | Article |
|---|---|
| Title: | Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction |
| Creators Name: | Schiattarella, G.G. and Altamirano, F. and Kim, S.Y. and Tong, D. and Ferdous, A. and Piristine, H. and Dasgupta, S. and Wang, X. and French, K.M. and Villalobos, E. and Spurgin, S.B. and Waldman, M. and Jiang, N. and May, H.I. and Hill, T.M. and Luo, Y. and Yoo, H. and Zaha, V.G. and Lavandero, S. and Gillette, T.G. and Hill, J.A. |
| Abstract: | 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. |
| Keywords: | Base Sequence, Binding Sites, Biological Models, Cardiac Myocytes, Conserved Sequence, Forkhead Box Protein O1, Gene Deletion, Genetic Transcription, HEK293 Cells, Heart Failure, Heart Ventricles, Inbred C57BL Mice, Lipid Metabolism, Myocardial Contraction, Myocardium, Phenotype, Protein Stability, Proteolysis, Stroke Volume, Ubiquitin-Protein Ligases, X-Box Binding Protein 1, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| Page Range: | 1684 |
| Date: | 16 March 2021 |
| Official Publication: | https://doi.org/10.1038/s41467-021-21931-9 |
| PubMed: | View item in PubMed |
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