Coactivator P300 promotes hepatic steatosis in obesity

共激活剂 P300 促进肥胖患者的肝脂肪变性

基本信息

批准号：
10365981
负责人：
Ling He
金额：
$ 53.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365981
关键词：
Acetylation Acetyltransferase Affect Binding Chemicals Data Deacetylase Defect Development Diabetes Mellitus Disease Resistance Dose E1A-associated p300 protein Epidemic Fatty Liver Fatty acid glycerol esters Gene Expression Genetic Goals Hepatic Hepatocyte High Fat Diet Hyperglycemia IRS1 gene IRS2 gene Impairment Inflammatory Insulin Receptor Insulin Resistance Insulin Signaling Pathway Knockout Mice Knowledge Link Liver Lysine Maps Mediating Mediator of activation protein Metabolic Metabolic Diseases Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obese Mice Obesity Overnutrition Pathway interactions Patients Play Population Proteins Resveratrol Risk Role SIRT1 gene Site Testing Therapeutic Tissues Triglycerides Tyrosine Phosphorylation biological adaptation to stress cytokine endoplasmic reticulum stress experimental study fatty liver disease genetic inhibitor glucose metabolism improved in vivo inhibitor insulin sensitivity insulin signaling lipid biosynthesis lipid metabolism negative affect new therapeutic target non-alcoholic fatty liver disease novel obese patients overexpression p300/CBP-Associated Factor prevent small hairpin RNA therapeutic target

项目摘要

Obesity, which has reached epidemic proportions worldwide, is associated with an increased risk of numerous metabolic abnormalities including nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). NAFLD is increasingly common, and now affects over 30% of the population in the USA. Insulin resistance is a hallmark of type 2 diabetes and obesity, and excessive accumulation of triglycerides is a hallmark of NAFLD. Because intact insulin signaling is required for lipogenesis, the defect in insulin signaling should reduce hepatic triglyceride content; however, patients with obesity and type 2 diabetes commonly have nonalcoholic fatty liver disease (NAFLD), and the majority of patients with NAFLD are also obese and/or have T2D. The underlying mechanisms leading to the paradoxical co-occurrence of hepatic steatosis and insulin resistance are not well understood. Previous studies have shown that overexpression of the deacetylase Sirtuin 1 or treatment with resveratrol, a Sirtuin 1 activator, not only improved hepatic steatosis, but also restored insulin sensitivity in tissues with insulin resistance. These results suggest that an acetyltransferase can antagonize Sirtuin 1’s activity, causing hepatic steatosis and insulin resistance. We observed a significant increase in hepatic acetyltransferase P300’s protein levels in high-fat diet (HFD) fed mice and ob/ob mice through the IRE1-XBP1s pathway in the endoplasmic reticulum stress response. Depletion of P300 or inhibition of P300 acetyltransferase activity decreased lipogenic gene expression and increased insulin sensitivity. Therefore, P300 uniquely increases lipogenesis and disrupts insulin signaling in the liver of obesity. We will assess the role of elevated P300 in promoting hepatic lipogenesis in Aim 1. We will define the molecular mechanisms of P300’s promotion of hepatic steatosis in Aim 2. We propose to determine whether P300 acetyltransferase activity is a therapeutic target for obesity/T2D in Aim 3. We believe that P300 plays an important role in the development of NAFLD and insulin resistance, linking inflammatory and metabolic diseases.

肥胖在世界范围内已达到流行病的程度，与许多疾病的风险增加有关代谢异常，包括非酒精性脂肪肝 (NAFLD) 和 2 型糖尿病 (T2D)。胰岛素抵抗越来越普遍，目前影响着超过 30% 的美国人口。 2 型糖尿病和肥胖的共同特点是甘油三酯过度积累是 NAFLD 的一个标志。脂肪生成需要完整的胰岛素信号传导，胰岛素信号传导的缺陷会降低肝脏甘油三酯然而，肥胖和 2 型糖尿病患者通常患有非酒精性脂肪肝。 (NAFLD)，并且大多数 NAFLD 患者也肥胖和/或患有 T2D。导致肝脂肪变性和胰岛素抵抗矛盾同时发生的原因尚不清楚。先前的研究表明，去乙酰化酶 Sirtuin 1 的过度表达或白藜芦醇治疗会导致 Sirtuin 1激活剂，不仅可以改善肝脏脂肪变性，还可以恢复胰岛素组织的胰岛素敏感性这些结果表明乙酰转移酶可以拮抗 Sirtuin 1 的活性，从而引起肝损伤。我们观察到肝乙酰转移酶 P300 蛋白显着增加。高脂饮食 (HFD) 喂养的小鼠和 ob/ob 小鼠中的水平通过内质中的 IRE1-XBP1s 途径 P300 的耗竭或 P300 乙酰转移酶活性的抑制会降低脂肪生成。基因表达和增加胰岛素敏感性因此，P300 独特地增加脂肪生成并破坏。肥胖肝脏中的胰岛素信号传导我们将评估升高的 P300 在促进肝脏脂肪生成中的作用。在目标1中，我们将在目标2中定义P300促进肝脂肪变性的分子机制。我们建议确定 P300 乙酰转移酶活性是否是目标 3 中肥胖/T2D 的治疗靶点。我们相信 P300 在 NAFLD 和胰岛素抵抗的发展中发挥着重要作用，将炎症和胰岛素抵抗联系起来代谢性疾病。