@article{82ff15e1bc4f4dfe989959031bd34618,
title = "Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction",
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.",
author = "Schiattarella, {Gabriele G.} and Francisco Altamirano and Kim, {Soo Young} and Dan Tong and Anwarul Ferdous and Hande Piristine and Subhajit Dasgupta and Xuliang Wang and French, {Kristin M.} and Elisa Villalobos and Spurgin, {Stephen B.} and Maayan Waldman and Nan Jiang and May, {Herman I.} and Hill, {Theodore M.} and Yuxuan Luo and Heesoo Yoo and Zaha, {Vlad G.} and Sergio Lavandero and Gillette, {Thomas G} and Hill, {Joseph A.}",
note = "Funding Information: We thank all members of the Hill laboratory for constructive discussion. We thank members of the Szweda Lab at UT Southwestern for their expertize in mitochondrial biology. We thank Dr. Xiang Luo for isolation of NRVMs. This work was supported by grants from the NIH: HL-120732 (JAH), HL-128215 (JAH), HL-126012 (JAH), HL-147933, (JAH), HL-155765 (JAH), F32HL136151 (KMF), F32HL142244 (DT), American Heart Association (AHA) 16POST30680016 and 19CDA34680003 (FA), 16PRE29660003 (SYK), 14SFRN20510023 (JAH), 14SFRN20670003 (JAH), AHA and the Theodore and Beulah Beasley Foundation grant 18POST34060230 (GGS), Fondation Leducq grant number 11CVD04 (JAH), Cancer Prevention and Research Institute of Texas grant RP110486P3 (JAH) and RP180404 (VGZ) and by Agencia Nacional de Investigacion y Desarrollo (ANID, Chile), FONDAP 15130011 and FONDECYT 1200490 (SL). Images in Fig. 6 were adapted from vectors available at Servier Medical Art (https://smart.servier.com/). Servier Medical Art is licensed under a Creative Commons Attribution 3.0 Unported Licence (https://creativecommons.org/licenses/by/3.0/). Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-21931-9",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}