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

• Published in: Nature communications Vol. 12; no. 1; pp. 1684 - 14
• Main Authors: Schiattarella, Gabriele G., Altamirano, Francisco, Kim, Soo Young, Tong, Dan, Ferdous, Anwarul, Piristine, Hande, Dasgupta, Subhajit, Wang, Xuliang, French, Kristin M., Villalobos, Elisa, Spurgin, Stephen B., Waldman, Maayan, Jiang, Nan, May, Herman I., Hill, Theodore M., Luo, Yuxuan, Yoo, Heesoo, Zaha, Vlad G., Lavandero, Sergio, Gillette, Thomas G., Hill, Joseph A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/1; 38/15; 38/89; 631/80/86; 692/4019/592/75/230; Accumulation; Animals; Base Sequence; Binding Sites; Cardiomyocytes; Congestive heart failure; Conserved Sequence; Depletion; Ejection fraction; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; Gene Deletion; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Ventricles - pathology; Heart Ventricles - physiopathology; HEK293 Cells; Homeostasis; Homology; Humanities and Social Sciences; Humans; Lipid Metabolism; Lipids; Metabolism; Mice; Mice, Inbred C57BL; Models, Biological; multidisciplinary; Muscle contraction; Myocardial Contraction; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Overexpression; Pathogenesis; Perturbation; Phenotype; Phenotypes; Proteasomes; Protein folding; Protein Stability; Proteins; Proteolysis; Science; Science (multidisciplinary); Steatosis; Stroke Volume; Transcription factors; Transcription, Genetic; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; X-Box Binding Protein 1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21931-9

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.