Case Cardiovascular Research Institute and Harrington Heart & Vascular Institute, Cleveland, OH 44106, USA ; Department of Medicine, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
PPAR Res. 2015;2015:201625. doi: 10.1155/2015/201625. Epub 2015 Feb 26.
The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARα) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARα operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARα-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARα and provides fundamental insights into the molecular regulation of cardiac lipid metabolism.
代谢心肌是杂食动物，利用各种碳源来满足其能量需求。虽然成年心脏优先利用脂肪酸 (FAs) 而非碳水化合物，但心肌燃料的可塑性对于机体的生存至关重要。这种调节燃料利用的代谢可塑性受到强大的转录控制，过去十年的研究阐明了核受体家族因素（如 PPARα）是心肌脂代谢的重要调节剂。然而，鉴于健康和疾病中心肌代谢的复杂性，很可能存在其他分子途径在起作用，阐明这些途径可能为新的治疗方法提供基础。我们之前证明了 Kruppel 样因子 15（KLF15）是心脏脂代谢的独立调节剂，这就提出了 KLF15 和 PPARα 可能以协调的方式共同作用，调节脂质氧化所必需的心肌基因表达的可能性。在本研究中，我们表明 KLF15 与 PPARα 结合、合作，并在诱导经典的 PPARα 介导的基因表达和心肌细胞中的脂质氧化中是必需的。因此，本研究建立了一个涉及 KLF15 和 PPARα 的分子模块，并为心脏脂代谢的分子调控提供了基本的见解。
