Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15.
Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15.
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轻相泼尼松通过心肌细胞特异性 GR 和 KLF15 的新型反式激活靶点促进心脏中的葡萄糖氧化。
DOI：
10.1101/2023.12.18.572210
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Quattrocelli,Mattia
中科院分区：
文献类型：
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作者：
ElAbdellaouiSoussi,Fadoua;Durumutla,HimaBindu;Latimer,Hannah;Prabakaran,AshokDaniel;McFarland,Kevin;Miz,Karen;Piczer,Kevin;Werbrich,Cole;Jain,MukeshK;Haldar,SaptarsiM;Quattrocelli,Mattia
昼夜摄取时间门糖皮质激素对健康和梗死心脏的心脏保护作用。心肌细胞特异性糖皮质激素受体(GR)及其辅因子Krüppel样因子(Klf15)在长期维持正常心功能中起着关键作用，是心脏代谢的多效性调节因子。尽管有这样的理解，但受GR-Klf15轴协同表观遗传作用影响的心肌细胞自主代谢靶点仍未确定。在这里，我们展示了心肌细胞特有的GR和KLF15在心脏内协调昼夜依赖的葡萄糖氧化程序中的关键作用。结合整合的转录组学和表观基因组学，结合心肌细胞特异性诱导的GR或KLF15的消融，我们确定了它们在脂联素受体表达(AdipoR1)和线粒体丙酮酸复合体(Mpc1/2)激活中的协同作用，从而促进胰岛素刺激的葡萄糖摄取和丙酮酸氧化。此外，在表现出胰岛素抵抗和葡萄糖氧化受损的肥胖糖尿病(db/db)小鼠中，与暗阶段服用泼尼松相反，轻度服用泼尼松有效地恢复了心肌细胞的葡萄糖氧化，并以一种性别无关的方式改善了向类似对照水平的舒张期功能。总而言之，我们的发现揭示了GR-Klf15轴的新的心肌细胞自主代谢靶点。这项研究强调了糖皮质激素对心肌细胞葡萄糖代谢的昼夜依赖性的心脏保护作用，为心血管疾病中糖皮质激素治疗的时序药理学策略提供了重要的见解。
Circadian time-of-intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its co-factor, Krüppel-like factor (Klf15), play critical roles in maintaining normal heart function in the long-term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of GR-Klf15 axis remain undefined. Here, we demonstrate the critical roles of the cardiomyocyte-specific GR and Klf15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or Klf15, we identified their synergistic role in the activation of adiponectin receptor expression (Adipor1) and the mitochondrial pyruvate complex (Mpc1/2), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic (db/db) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, effectively restored cardiomyocyte glucose oxidation and improved diastolic function towards control-like levels in a sex-independent manner. Collectively, our findings uncover novel cardiomyocyte-autonomous metabolic targets of the GR-Klf15 axis. This study highlights the circadian-dependent cardioprotective effects of glucocorticoids on cardiomyocyte glucose metabolism, providing critical insights into chrono-pharmacological strategies for glucocorticoid therapy in cardiovascular disease.