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

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.

肥胖症在全世界已达到流行病的程度， 代谢异常，包括非酒精性脂肪肝（NAFLD）和2型糖尿病（T2 D）。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 2型糖尿病和肥胖症的一个重要特征是甘油三酯的过度积累。因为 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应减少肝脏甘油三酯 然而，肥胖和2型糖尿病患者通常患有非酒精性脂肪肝疾病， NAFLD是一种非酒精性脂肪性肝病（NAFLD），并且大多数NAFLD患者也是肥胖和/或患有T2 D。潜在的机制 导致肝脂肪变性和胰岛素抵抗的矛盾共存的原因还不清楚。 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， Sirtuin 1激活剂不仅改善了肝脏脂肪变性，而且还恢复了胰岛素敏感性 阻力这些结果表明乙酰转移酶可以拮抗Sirtuin 1的活性，引起肝细胞凋亡。 脂肪变性和胰岛素抵抗。我们观察到肝乙酰转移酶P300蛋白的显著增加 高脂饮食（HFD）喂养小鼠和ob/ob小鼠中通过内质网中的IRE 1-XBP 1 s途径的水平 网状应激反应耗尽P300或抑制P300乙酰转移酶活性可降低脂肪生成 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 胰岛素信号在肝脏中的作用。我们将评估升高的P300在促进肝脏脂肪生成中的作用。 目标1。我们将在目标2中明确P300促进肝脂肪变性的分子机制。我们提出 以确定P300乙酰转移酶活性是否是目标3中肥胖/T2 D的治疗靶标。我们认为 P300在NAFLD和胰岛素抵抗的发展中起着重要作用，将炎症和胰岛素抵抗联系起来。 代谢性疾病