Sugi Keiki, Hsieh Paishiun N, Ilkayeva Olga, Shelkay Shamanthika, Moroney Bridget, Baadh Palvir, Haynes Browning, Pophal Megan, Fan Liyan, Newgard Christopher B, Prosdocimo Domenick A, Jain Mukesh K
Case Cardiovascular Research Institute and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, United States of America.
Department of Medicine, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, United States of America.
PLoS One. 2018 Feb 6;13(2):e0192376. doi: 10.1371/journal.pone.0192376. eCollection 2018.
Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARα. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization.
心脏代谢对底物可用性的变化具有高度适应性，比如在禁食期间所发生的变化。这种代谢灵活性对于维持收缩功能至关重要，并且受一组特定转录调节因子的控制，尤其是核受体家族因子成员PPARα。然而，心脏必须维持功能所经历的生理和病理状态的多样性表明，可能存在其他转录调节因子，它们在使心脏代谢与能量需求相匹配方面发挥作用。在此我们表明，心脏KLF15是心脏对禁食的正常反应所必需的。具体而言，我们发现，在全身和心脏特异性Klf15基因敲除小鼠中，禁食时心脏功能受损。此外，心脏特异性Klf15基因敲除小鼠表现出长链酰基肉碱类物质的禁食依赖性积累，同时肉碱转运体Slc25a20的表达降低。用高短链脂肪酸饮食进行治疗可缓解禁食时KLF15依赖性长链酰基肉碱积累及心脏功能受损的情况。我们的观察结果确立了KLF15作为心脏对禁食适应性反应的关键介质，通过其对心肌脂质利用的调节作用。
