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:9755549
- 负责人:
- 金额:$ 57.13万
- 依托单位:
- 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:
- 关键词:AcetylationAcetyltransferaseAffectBindingChemicalsDataDeacetylaseDefectDevelopmentDiabetes MellitusDisease ResistanceDoseE1A-associated p300 proteinEpidemicFatty LiverFatty acid glycerol estersGene ExpressionGeneticGoalsHepaticHepatocyteHigh Fat DietHyperglycemiaIRS1 geneIRS2 geneImpairmentInflammatoryInsulin ReceptorInsulin ResistanceInsulin Signaling PathwayKnockout MiceKnowledgeLinkLiverLiver diseasesLysineMapsMediatingMediator of activation proteinMetabolicMetabolic DiseasesMolecularMusNon-Insulin-Dependent Diabetes MellitusNuclearObese MiceObesityOvernutritionPathway interactionsPatientsPlayPopulationProteinsResveratrolRiskRoleSIRT1 geneSiteTestingTherapeuticTissuesTriglyceridesTyrosine Phosphorylationbiological adaptation to stresscytokineendoplasmic reticulum stressexperimental studygenetic inhibitorglucose metabolismimprovedin vivoinhibitor/antagonistinsulin sensitivityinsulin signalinglipid biosynthesislipid metabolismnegative affectnew therapeutic targetnon-alcoholic fatty liver diseasenoveloverexpressionp300/CBP-Associated Factorpreventsmall hairpin RNAtherapeutic 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。
项目成果
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{{ truncateString('Ling He', 18)}}的其他基金
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 - 财政年份:2019
- 资助金额:
$ 57.13万 - 项目类别:
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:
10597095 - 财政年份:2019
- 资助金额:
$ 57.13万 - 项目类别:
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:
10365981 - 财政年份:2019
- 资助金额:
$ 57.13万 - 项目类别:
Activation of the cAMP-PKA pathway antagonizes metformin action
cAMP-PKA 通路的激活会拮抗二甲双胍的作用
- 批准号:
9186543 - 财政年份:2015
- 资助金额:
$ 57.13万 - 项目类别:
Activation of the cAMP-PKA pathway antagonizes metformin action
cAMP-PKA 通路的激活会拮抗二甲双胍的作用
- 批准号:
9008164 - 财政年份:2015
- 资助金额:
$ 57.13万 - 项目类别:
The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production
CBP 和 p300 在调节肝葡萄糖生成中的独特作用
- 批准号:
8310339 - 财政年份:2011
- 资助金额:
$ 57.13万 - 项目类别:
The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production
CBP 和 p300 在调节肝葡萄糖生成中的独特作用
- 批准号:
8328726 - 财政年份:2011
- 资助金额:
$ 57.13万 - 项目类别:
The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production
CBP 和 p300 在调节肝葡萄糖生成中的独特作用
- 批准号:
8515392 - 财政年份:2011
- 资助金额:
$ 57.13万 - 项目类别:
The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production
CBP 和 p300 在调节肝葡萄糖生成中的独特作用
- 批准号:
7989326 - 财政年份:2010
- 资助金额:
$ 57.13万 - 项目类别:
The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production
CBP 和 p300 在调节肝葡萄糖生成中的独特作用
- 批准号:
8115793 - 财政年份:2010
- 资助金额:
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