Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.
Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.
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DOI：
10.1038/s41467-021-21931-9
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发表时间：
2021-03-16
影响因子：
16.6
通讯作者：
Hill JA
中科院分区：
文献类型：
--
作者：
Schiattarella GG;Altamirano F;Kim SY;Tong D;Ferdous A;Piristine H;Dasgupta S;Wang X;French KM;Villalobos E;Spurgin SB;Waldman M;Jiang N;May HI;Hill TM;Luo Y;Yoo H;Zaha VG;Lavandero S;Gillette TG;Hill JA
射血分数保留的心力衰竭(HFpEF)目前是心力衰竭的主要形式，目前还没有有效的治疗方法。肥胖和血脂处理不当极大地促进了HFpEF。然而，高压性高血压患者代谢改变和脂质平衡紊乱的分子机制(S)尚不清楚。在这里，我们报告了HFpEF中的心肌细胞脂肪变性伴随着转录因子FoxO1(叉头盒蛋白O1)活性的增加。在心肌细胞中，Foxo1的耗尽以及UPR(未折叠蛋白反应)的Xbp1s(剪接形式的X盒结合蛋白1)臂的过度表达都可以改善小鼠的HFpEF表型，并减少心肌脂质的积累。在机制上，Xbp1s在心肌细胞中的强制表达触发了FoxO1的泛素化和蛋白酶体降解，这在很大程度上是通过激活E3泛素连接酶STUB1(STIP1同源和U-box包含蛋白1)来实现的，STUB1是Xbp1s的新的直接转录靶点。我们的发现揭示了Xbp1s-FoxO1轴是心脏代谢性HFpEF发病的关键机制，并揭示了先前未知的UPR调控心肌细胞代谢变化的机制。射血分数保留的心力衰竭(HFpEF)是一个全球性的重大健康问题，目前还没有有效的治疗方法。在这里，作者发现两个转录因子Xbp1s和FoxO1之间的相互作用对于HFpEF应激心肌细胞的代谢适应和脂质处理至关重要。
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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DOI：
10.3390/molecules23061479
发表时间：
2018-06-19
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Lambert M;Jambon S;Depauw S;David-Cordonnier MH
通讯作者：
David-Cordonnier MH
影响因子：
5.2
作者：
Glimcher LH;Lee AH
通讯作者：
Lee AH
影响因子：
20.1
作者：
Kolwicz SC Jr;Olson DP;Marney LC;Garcia-Menendez L;Synovec RE;Tian R
通讯作者：
Tian R
影响因子：
37.8
作者：
Kim SY;Zhang X;Schiattarella GG;Altamirano F;Ramos TAR;French KM;Jiang N;Szweda PA;Evers BM;May HI;Luo X;Li H;Szweda LI;Maracaja-Coutinho V;Lavandero S;Gillette TG;Hill JA
通讯作者：
Hill JA
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.