Role of KLF5 in cardiac and systemic fatty acid metabolism

KLF5 在心脏和全身脂肪酸代谢中的作用

基本信息

批准号：
9919371
负责人：
Konstantinos Drosatos
金额：
$ 39万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919371
关键词：
18 year old Ablation Address Adipocytes Adipose tissue Adult Affect Animal Genetics Animal Model Binding Sites Biological Body Weight Body Weights and Measures Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cells Ceramides Consumption DNA Binding Data Death Rate Dependovirus Development Diabetes Mellitus Diabetic mouse Diagnosis Diet Diglycerides Disease Eating FGF21 gene FOXO1A gene Fatty acid glycerol esters Fibroblast Growth Factor Gene Delivery Gene Expression Generations Genetic Transcription Glucose Heart Heart failure Hyperglycemia In Vitro Injections Insulin Resistance Insulin deficiency Knockout Mice Link Lipids Measurement Measures Mediating Metabolic Metabolism Methods Mitochondria Molecular Morphology Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Obese Mice Obesity Organ PPAR alpha PPAR gamma Pathology Pathway interactions Pharmacology Plasma Proteins RNA Polymerase II Reactive Oxygen Species Research Role Signal Transduction Site Source Streptozocin Transcription Coactivator Triglycerides Weight Gain adipocyte differentiation adult obesity chromatin immunoprecipitation cost diabetic diabetic cardiomyopathy fatty acid metabolism fatty acid oxidation heart function hospitalization rates in silico in vivo inhibitor/antagonist insight insulin signaling lipid biosynthesis lipid metabolism neutralizing antibody new therapeutic target novel obesity prevention preference prevent promoter public health relevance transcription factor

项目摘要

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.

描述（由申请人提供）：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中脂质代谢和心脏功能障碍的变化有关。肥胖会导致心脏脂质积聚，也称为脂毒性，并导致心脏功能障碍，但体外研究表明，心脏影响全身代谢的机制尚不清楚。体内初步数据确定心脏 Krϋppel 样因子 5 (KLF5) 是 Ppara 和 Med13 的转录激活因子，因此，心脏 KLF5 成为心脏 FFA 和全身代谢的新调节因子。高血糖导致Ppara表达和心脏FAO相关基因表达减少。我们的数据表明心脏FOXO1是Klf5的抑制剂。心肌细胞的抑制会加速饮食诱导的肥胖 (DIO)，这种体重增加的变化与心脏功能的降低或食物摄入量和小鼠活动的改变无关，但与白色小鼠中心脏和血浆 FGF21 的增加以及 PPARγ 的 SUMO 化有关。脂肪组织，这表明 PPARγ 活性增加，促进脂肪细胞发育。我们发现心肌细胞 Klf5 激活将导致心脏 F0O 的联合激活，并抑制心脏脂质积累和肥胖。阐明高血糖与心脏 Klf5、Ppara 和 FAO 相关基因表达抑制之间的联系机制，以及心脏 KLF5 调节 DIO 的途径。我们还旨在将 Klf5 激活应用于心肌细胞，作为增加心脏 FAO 和减少的一种方法。为了解决这些问题，我们提出以下具体目标：目标 1 - 确定糖尿病如何抑制心脏 Klf5 和 Ppara 表达目标 2 - 确定如何抑制心脏 Klf5 和 Ppara 表达。心肌细胞 Klf5 消融信号系统性地促进 DIO 目标 3 - 研究心肌细胞 Klf5 激活如何预防肥胖动物模型中的心脏脂毒性和 WAT 发育。