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.
Highlights
Heart failure with preserved ejection fraction (HFpEF) is the dominant form of heart failure and one for which no efficacious therapies exist
Surveying the gene promoter regions of the ubiquitin ligases known to be involved in FoxO1 degradation, we identified a conserved unfolded protein response (UPR) element (UPRE) nucleotide sequence—the prototypical binding site of Xbp1s—in the promoter region of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-Box-containing protein 1) (Fig. 4a)
We employed a clinically relevant murine model of cardiometabolic HFpEF and made a series of novel mechanistic observations: (1) Xbp1s, which is decreased in HFpEF9, reduces myocardial lipid accumulation; (2) FoxO1 promotes lipid accumulation in HFpEF cardiomyocytes; (3) Xbp1s promotes FoxO1 protein degradation; (4) cardiomyocyte-specific deletion of FoxO1 ameliorates the HFpEF phenotype and diminishes cardiac steatosis; (5) the E3 ubiquitin ligase STUB1, a direct transcriptional target of Xbp1s, is downregulated in HFpEF and governs FoxO1 stability in cardiomyocytes
Summary
Heart failure with preserved ejection fraction (HFpEF) is the dominant form of heart failure and one for which no efficacious therapies exist. Molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. 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. In striking contrast with the other major form of HF—HF with reduced ejection fraction, HFrEF—the incidence and prevalence of HFpEF have increased steadily over the last decade. Despite the wellrecognized association between obesity and HFpEF, mechanistic elements governing the excess lipid accumulation in cardiomyocytes—i.e. cardiac lipid overload—are poorly understood
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