心肌细胞KLF5调节过氧化物酶体增殖物激活受体α（Ppara）的表达及心脏功能。
Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function.
作者信息
Drosatos Konstantinos, Pollak Nina M, Pol Christine J, Ntziachristos Panagiotis, Willecke Florian, Valenti Mesele-Christina, Trent Chad M, Hu Yunying, Guo Shaodong, Aifantis Iannis, Goldberg Ira J
机构信息
From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
出版信息
Circ Res. 2016 Jan 22;118(2):241-53. doi: 10.1161/CIRCRESAHA.115.306383. Epub 2015 Nov 16.
RATIONALE
Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown.
OBJECTIVE
To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara.
METHODS AND RESULTS
We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels.
CONCLUSIONS
Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.
原理
脂肪酸氧化受过氧化物酶体增殖物激活受体（PPAR）α转录调控，在正常情况下占心脏ATP含量的70%。脓毒症和心力衰竭期间Ppara表达降低会导致脂肪酸氧化减少和心肌能量缺乏。Ppara的许多转录调节因子尚不清楚。
目的
确定Krüppel样因子5（KLF5）在Ppara转录调控中的作用。
方法与结果
我们发现KLF5通过直接结合启动子激活Ppara基因表达。在脓毒症小鼠心脏中，这一过程被c-Jun阻断，c-Jun结合Ppara启动子上的重叠位点并减少转录。我们构建了心肌细胞特异性Klf5基因敲除小鼠，这些小鼠心脏中Ppara及其下游脂肪酸代谢相关靶点的表达降低。这些变化与心脏脂肪酸氧化减少、ATP水平降低、甘油三酯积累增加和心脏功能障碍有关。糖尿病小鼠心脏中Klf5和Ppara表达水平呈现类似变化。
结论
心肌细胞KLF5是Ppara和心脏能量代谢的转录调节因子。
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