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