Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction

Gabriele G. Schiattarella, Francisco Altamirano, Soo Young Kim, Dan Tong, Anwarul Ferdous, Hande Piristine, Subhajit Dasgupta, Xuliang Wang, Kristin M. French, Elisa Villalobos, Stephen B. Spurgin, Maayan Waldman, Nan Jiang, Herman I. May, Theodore M. Hill, Yuxuan Luo, Heesoo Yoo, Vlad G. Zaha, Sergio Lavandero, Thomas G. Gillette and Joseph A. Hill ()
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Gabriele G. Schiattarella: University of Texas Southwestern Medical Center
Francisco Altamirano: University of Texas Southwestern Medical Center
Soo Young Kim: University of Texas Southwestern Medical Center
Dan Tong: University of Texas Southwestern Medical Center
Anwarul Ferdous: University of Texas Southwestern Medical Center
Hande Piristine: University of Texas Southwestern Medical Center
Subhajit Dasgupta: University of Texas Southwestern Medical Center
Xuliang Wang: University of Texas Southwestern Medical Center
Kristin M. French: University of Texas Southwestern Medical Center
Elisa Villalobos: University of Texas Southwestern Medical Center
Stephen B. Spurgin: University of Texas Southwestern Medical Center
Maayan Waldman: University of Texas Southwestern Medical Center
Nan Jiang: University of Texas Southwestern Medical Center
Herman I. May: University of Texas Southwestern Medical Center
Theodore M. Hill: University of Texas Southwestern Medical Center
Yuxuan Luo: University of Texas Southwestern Medical Center
Heesoo Yoo: University of Texas Southwestern Medical Center
Vlad G. Zaha: University of Texas Southwestern Medical Center
Sergio Lavandero: University of Texas Southwestern Medical Center
Thomas G. Gillette: University of Texas Southwestern Medical Center
Joseph A. Hill: University of Texas Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21931-9

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