Role of KLF5 in cardiac and systemic fatty acid metabolism

 描述（由申请方提供）：脂肪酸氧化由过氧化物酶体增殖物激活受体α（PPARα）转录调节，产生70%的心脏ATP。Ppara表达的改变与糖尿病和肥胖症中脂质代谢和心功能障碍的变化相关。肥胖导致心脏脂质积聚，也称为脂毒性，并导致心脏功能障碍。一些研究表明，心脏影响全身代谢的机制尚不清楚。我们在体外和体内的初步数据确定心脏KLF样因子5（KLF 5）作为Ppara和Med 13的转录激活因子。因此，心脏KLF 5成为心脏FAO和全身代谢的新调节剂。我们发现，心脏Klf 5的表达被高血糖抑制，导致Ppara表达和心脏FAO相关基因表达降低。我们的数据表明心脏FOXO 1是Klf 5的抑制剂。此外，我们还发现心肌细胞中的KLF 5抑制加速了饮食诱导的肥胖（DIO）。体重增加的这种变化与心脏功能降低或食物摄入量和小鼠活动改变无关。然而，它与心脏和血浆FGF 21增加以及白色脂肪组织中PPARγ SUMO化减少相关，这表明促进脂肪细胞发育的PPARγ活性增加。我们假设，心肌细胞Klf 5激活将导致心脏FAO的联合激活和心脏脂质积聚和肥胖的抑制。我们的研究旨在阐明高血糖与心脏Klf 5，Ppara和FAO相关基因表达抑制的机制，以及心脏KLF 5调节DIO的途径。我们还旨在将Klf 5激活应用于心肌细胞中，作为增加肥胖小鼠心脏FAO和减少脂肪储存的一种方式。为了解决这些问题，我们提出了以下具体目标：目标1 -确定糖尿病如何抑制心脏Klf 5和Ppara表达。目的2 -确定心肌细胞Klf 5消融如何系统地发出信号以促进DIO。目的3 -研究心肌细胞Klf 5激活如何在肥胖动物模型中预防心脏脂毒性和WAT的发展。

 DESCRIPTION (provided by applicant): Fatty acid oxidation, which is transcriptionally regulated by Peroxisome proliferator-activated receptor α (PPARα), produces 70% of cardiac ATP. Alterations in Ppara expression have been associated with changes in lipid metabolism and cardiac dysfunction in diabetes and obesity. Obesity leads to cardiac lipid accumulation, also known as lipotoxicity and causes cardiac dysfunction. Several studies have shown that the heart affects systemic metabolism by mechanisms that remain unclear. Our in vitro and in vivo preliminary data identify cardiac Krϋppel-like factor 5 (KLF5) as a transcriptional activator of both Ppara and Med13. Thus, cardiac KLF5 emerges as a new regulator of cardiac FAO and systemic metabolism. We show that cardiac Klf5 expression is inhibited by hyperglycemia leading to reduced Ppara expression and cardiac FAO-related gene expression. Our data implicate cardiac FOXO1 as an inhibitor of Klf5. In addition, we show that KLF5 inhibition in cardiomyocytes accelerates diet-induced obesity (DIO). This change in weight gain is not associated either with reduced cardiac function or altered food intake and mouse activity. It is however associated with increased cardiac and plasma FGF21 and reduced SUMOylation of PPARγ in white adipose tissue, which indicates increased PPARγ activity that promotes adipocyte development. We hypothesize that cardiomyocyte Klf5 activation will lead to combined activation of cardiac FAO and inhibition of cardiac lipid accumulation and obesity. Our proposed research aims to elucidate the mechanism that links hyperglycemia with inhibition of cardiac Klf5, Ppara and FAO-related gene expression, as well as the pathway via which cardiac KLF5 regulates DIO. We also aim to apply Klf5 activation in cardiomyocytes as a way to increase cardiac FAO and reduce fat storage in obese mice. To address these questions we propose the following specific aims: Aim 1 - To determine how diabetes inhibits cardiac Klf5 and Ppara expression. Aim 2 - To identify how cardiomyocyte Klf5 ablation signals systemically to promote DIO. Aim 3 - To investigate how cardiomyocyte Klf5 activation can prevent both cardiac lipotoxicity and WAT development in animal models of obesity.