Role of Dach1 in Obesity-Induced Hepatic Insulin Resistance

Dach1 在肥胖引起的肝胰岛素抵抗中的作用

• 批准号: 9316590
• 负责人: Lale Ozcan
• 金额: $ 36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316590
• 关键词: ATF6 gene; Address; Binding; Calcium; Calcium/calmodulin-dependent protein kinase; Cardiovascular Diseases; Conceptions; Consensus; Data; Development; Disease; Engineering; Epidemic; Etiology; Euglycemic Clamping; Event; Exclusion; Eye diseases; Functional disorder; Genetic Transcription; HDAC4 gene; Half-Life; Hepatic; Hepatocyte; Histone Deacetylase; Homologous Gene; Human; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Receptor; Insulin Resistance; Kidney Failure; Knowledge; Link; Liver; Mediating; Metabolic; Metabolism; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Mus; Mutate; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Translocation; Obese Mice; Obesity; Pathway interactions; Process; Proteins; Publishing; Receptor Signaling; Reporter; Repression; Role; Series; Signal Transduction; Site; Specimen; Testing; Therapeutic; Therapeutic Intervention; Thinness; Treatment Efficacy; Work; calmodulin-dependent protein kinase II; glucose metabolism; glucose production; human subject; improved; in vivo; insight; insulin signaling; insulin tolerance; mortality; mutant; novel; novel therapeutic intervention; preclinical study; prevent; small hairpin RNA; treatment strategy

Excessive hepatic glucose production (HGP) and defective insulin signaling are critical in the development of type 2 diabetes (T2D). Over the past few years, our work has revealed new molecular pathways relevant to these two processes—pathways that we have shown recently in pre-clinical studies are amenable to a new type of therapy. We showed that obesity leads to the activation of a pathway initiated by calcium-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes (HCs). CaMKII suppresses an ATF6-protein chaperone module, which in turn activates a PERK-ATF4-Trb3 pathway that disrupts insulin receptor signaling. Our new data has revealed that hepatic CaMKII phosphorylates and blocks nuclear translocation of a class IIa histone deacetylase (HDAC4), which increases the level of a co- repressor called Dachshund homolog 1 (Dach1). Dach1, which has never before been implicated in metabolism, is dramatically increased in the livers of obese mice and humans and its inhibition in obese mice protects against hyperglycemia and hyperinsulinemia, identifying Dach1 as a critical link between obesity, insulin resistance, and metabolic dysfunction. We have proposed a series of studies to determine the mechanisms by which hepatocyte Dach1 deficiency improves insulin resistance in obesity (Aim 1) and to elucidate the proximal signaling events of how obesity regulates Dach1 and the downstream molecular mechanisms of Dach1-mediated suppression of insulin signaling (Aim 2). The involvement of hepatic Dach1 in the metabolic disturbances of obesity is a completely new and unexplored concept. We believe upon completion of the proposed studies, the integrated role of hepatic Dach1 in mediating insulin resistance through its effects on insulin signaling could reveal novel insights and provide therapeutic strategies for the treatment of T2D.

肝葡萄糖生成过多（HGP）和胰岛素信号传导缺陷对于糖尿病的发生至关重要。 过去几年，我们的工作揭示了 2 型糖尿病 (T2D) 的新进展。 与这两个过程相关的分子途径——我们最近在 临床前研究适合一种新型疗法，我们表明肥胖会导致肥胖。 由钙诱导的钙/钙调蛋白依赖性激活启动的途径的激活 肝细胞 (HC) 中的蛋白激酶 II (CaMKII) 抑制 ATF6 蛋白伴侣。 模块，进而激活 PERK-ATF4-Trb3 通路，破坏胰岛素受体 我们的新数据显示，肝脏 CaMKII 磷酸化并阻断核。 IIa 类组蛋白脱乙酰酶 (HDAC4) 的易位，增加了辅酶的水平 称为 Dachshund 同源物 1 (Dach1) 的阻遏蛋白，此前从未涉及过。 在新陈代谢中，在肥胖小鼠和人类的肝脏中显着增加，并且在 肥胖小鼠可预防高血糖和高胰岛素血症，将 Dach1 确定为关键蛋白 我们提出了一系列肥胖、胰岛素抵抗和代谢功能障碍之间的联系。 研究确定肝细胞 Dach1 缺乏改善胰岛素的机​​制 肥胖的抵抗力（目标 1）并阐明肥胖如何发生的近端信号事件 调节 Dach1 和 Dach1 介导的抑制的下游分子机制 胰岛素信号转导（目标 2）：肝脏 Dach1 参与代谢紊乱。 我们相信，肥胖是一个全新的、未经探索的概念。 研究表明，肝脏 Dach1 通过影响胰岛素抵抗来介导胰岛素抵抗的综合作用 胰岛素信号传导可以揭示新的见解并为治疗提供治疗策略 T2D。