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.

过度的肝葡萄糖产生（HGP）和缺陷的胰岛素信号在 2型糖尿病（T2D）的发展。在过去的几年中，我们的工作揭示了新的 与这两个过程相关的分子途径 - 我们最近在 临床前研究可以接受一种新型的治疗。我们表明肥胖导致 通过钙诱导的钙/钙调蛋白依赖性激活引发的途径的激活 肝细胞（HCS）中的蛋白激酶II（CAMKII）。 CAMKII抑制ATF6-蛋白链链 该模块又激活了破坏胰岛素受体的PERK-ATF4-TRB3途径 信号。我们的新数据表明，肝脏CAMKII磷酸化并阻止核 IIA类组蛋白脱乙酰基酶（HDAC4）的易位，这增加了共同的水平 压抑剂称为Dachshund同源1（DACH1）。 dach1，从来没有被牵涉过 在新陈代谢中，肥胖的老鼠和人类的生活及其抑制作用都大大增加 肥胖小鼠预防高血糖和高胰岛素血症，将DACH1识别为关键 肥胖，胰岛素抵抗和代谢功能障碍之间的联系。我们提出了一系列 研究确定肝细胞DACH1缺乏症的机制 肥胖症的抗性（AIM 1），并阐明肥胖的近端信号传导事件 调节DACH1和DACH1介导的抑制的下游分子机制 胰岛素信号传导（AIM 2）。肝Dach1参与的代谢灾害 肥胖是一个全新且出乎意料的概念。我们相信拟议的 研究，肝DACH1在介导胰岛素耐药性中的综合作用通过其对胰岛素耐药性的影响 胰岛素信号传导可以揭示新的见解，并提供治疗的治疗策略 T2D。