Coactivator P300 promotes hepatic steatosis in obesity

共激活剂 P300 促进肥胖患者的肝脂肪变性

• 批准号: 9902424
• 负责人: Ling He
• 金额: $ 54.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/9902424
• 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; Liver diseases; 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; genetic inhibitor; glucose metabolism; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; negative affect; new therapeutic target; non-alcoholic fatty liver disease; novel; overexpression; p300/CBP-Associated Factor; prevent; small hairpin RNA; therapeutic target; 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; Liver diseases; 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; genetic inhibitor; glucose metabolism; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; negative affect; new therapeutic target; non-alcoholic fatty liver disease; novel; overexpression; p300/CBP-Associated Factor; prevent; small hairpin RNA; therapeutic target

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.

肥胖症已达到全球流行比例，与许多人的风险增加有关 代谢异常，包括非酒精性脂肪肝病（NAFLD）和2型糖尿病（T2D）。 nafld 越来越普遍，现在影响了美国30％以上的人口。胰岛素抵抗是一个标志 2型糖尿病和肥胖症以及甘油三酸酯的过量积累是NAFLD的标志。因为 脂肪生成需要完整的胰岛素信号传导，胰岛素信号的缺陷应减少肝甘油三酸酯 内容;但是，肥胖症和2型糖尿病患者通常患有非酒精性脂肪肝病 （NAFLD），大多数NAFLD患者也肥胖和/或具有T2D。基本机制 导致肝脂肪变性和胰岛素抵抗的矛盾同时尚不清楚。 先前的研究表明，脱乙酰基酶Sirtuin 1或用白藜芦醇治疗A的过表达，A Sirtuin 1激活剂，不仅改善了肝脂肪变性，还可以恢复胰岛素的组织中的胰岛素敏感性 反抗。这些结果表明，乙酰转移酶可以拮抗Sirtuin 1的活性，从而导致肝 脂肪变性和胰岛素抵抗。我们观察到乙酰转移酶P300的蛋白质显着增加 高脂饮食中的水平（HFD）通过内皮塑料中的IRE1-XBP1S途径喂养小鼠和OB/OB/OB/OB/OB小鼠 网状应激反应。 p300的耗竭或抑制p300乙酰转移酶活性降低了脂肪生成 基因表达和胰岛素敏感性提高。因此，p300唯一增加了脂肪生成和破坏 肥胖症中的胰岛素信号传导。我们将评估升高p300在促进肝脂肪生成中的作用 在AIM 1中。我们将定义P300在AIM 2中促进肝脂肪变性的分子机制。我们提出 确定P300乙酰转移酶活性是否是AIM 3中肥胖/T2D的治疗靶标。我们相信 P300在NAFLD和胰岛素抵抗的发展中起着重要作用，将炎症和 代谢疾病。