Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction
Author
dc.contributor.author
Schiattarella, Gabriele G.
Author
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Altamirano, Francisco
Author
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Young Kim, Soo
Author
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Tong, Dan
Author
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Ferdous, Anwarul
Author
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Piristine, Hande
Author
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Dasgupta, Subhajit
Author
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Wang, Xuliang
Author
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French, Kristin M.
Author
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Villalobos, Elisa
Author
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Spurgin, Stephen B.
Author
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Waldman, Maayan
Author
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Jiang, Nan
Author
dc.contributor.author
May, Herman I.
Author
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Hill, Theodore M.
Author
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Luo, Yuxuan
Author
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Yoo, Heesoo
Author
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Zaha, Vlad G.
Author
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Lavandero González, Sergio Alejandro
Author
dc.contributor.author
Gillette, Thomas G.
Author
dc.contributor.author
Hill, Joseph A.
Admission date
dc.date.accessioned
2022-03-07T14:00:53Z
Available date
dc.date.available
2022-03-07T14:00:53Z
Publication date
dc.date.issued
2021
Cita de ítem
dc.identifier.citation
Nature Communications (2021) 12:1684
es_ES
Identifier
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10.1038/s41467-021-21931-9
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/184080
Abstract
dc.description.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. 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.
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Patrocinador
dc.description.sponsorship
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA HL-120732
HL-128215
HL-126012
HL147933
HL-155765
F32HL136151
F32HL142244
American Heart Association 16POST30680016
Aparece en contenido como:American Heart Association (AHA)
19CDA34680003
Aparece en contenido como:American Heart Association (AHA)
16PRE29660003
14SFRN20510023
Aparece en contenido como:American Heart Association (AHA)
14SFRN20670003
Aparece en contenido como:American Heart Association (AHA)
Theodore and Beulah Beasley Foundation 18POST34060230
Leducq Foundation 11CVD04
Cancer Prevention and Research Institute of Texas RP110486P3
RP180404
Agencia Nacional de Investigacion y Desarrollo (ANID, Chile)
FONDAP 15130011
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT 1200490
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Lenguage
dc.language.iso
en
es_ES
Publisher
dc.publisher
Nature
es_ES
Type of license
dc.rights
Attribution-NonCommercial-NoDerivs 3.0 United States