Coactivator P300 promotes hepatic steatosis in obesity

肥胖症在世界范围内已经达到流行的程度，它与患上 代谢异常包括非酒精性脂肪性肝病(NAFLD)和2型糖尿病(T2D)。NAFLD 这种病越来越普遍，目前影响着美国30%以上的人口。胰岛素抵抗是一个标志 2型糖尿病和肥胖症的发病率很高，而甘油三酯的过度积累是NAFLD的一个特征。因为 完整的胰岛素信号是脂肪生成所必需的，胰岛素信号的缺陷应该会降低肝脏甘油三酯 内容：然而，肥胖和2型糖尿病患者通常有非酒精性脂肪性肝病。 (NAFLD)，大多数NAFLD患者也是肥胖和/或患有T2D。潜在的机制 导致肝脏脂肪变性和胰岛素抵抗矛盾并存的原因尚不清楚。 先前的研究表明，脱乙酰酶Sirtuin 1的过度表达或白藜芦醇的治疗， Sirtuin 1激活剂，不仅改善了肝脏脂肪变性，而且还恢复了有胰岛素的组织的胰岛素敏感性 抵抗。这些结果表明，乙酰基转移酶可以拮抗Sirtuin1‘S活性，导致肝脏 脂肪变性和胰岛素抵抗。我们观察到肝脏乙酰转移酶P300‘S蛋白显著增加 高脂饮食(HFD)小鼠和肥胖/肥胖小鼠通过IRE1-XBP1s途径在内质中的水平 网状结构应激反应。P300的耗尽或P300乙酰转移酶活性的抑制可减少脂肪生成 基因表达和胰岛素敏感性增加。因此，P300独特地增加了脂肪生成并破坏了 肥胖患者肝脏中的胰岛素信号。我们将评估P300升高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中确定P300‘S促进肝脏脂肪变性的分子机制。 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。 P300在NAFLD的发展和胰岛素抵抗中发挥重要作用，将炎症和胰岛素抵抗联系起来 代谢性疾病。

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.