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Study on a novel energy metabolism transcription factor that regulates insulin signaling

调节胰岛素信号传导的新型能量代谢转录因子的研究

基本信息

批准号：
17390259
负责人：
SHIMANO Hitoshi
金额：
$ 9.92万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390259/
关键词：
insulin resistance Metabolic Syndrome Lifestyle-related diseases diabetes transcription factors insulin signaling IR52 TFE3

项目摘要

Genes involved in carbohydrate and lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion. SREBP-1c is a bHLH transcription factor that control lipogenesis and is induced during over-nutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of the excess energy. Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis, hypertriglyceridemia, and hepatic insulin resistance due to direct suppression of insulin signaling pathways, precipitating development of metabolic syndrome. Conversely, in an attempt to seek for a novel factor that could have therapeutic effects on obesity- or insulin resistance-related disorders, we identified TFE3, a novel bHLH transcription factor that activates various insulin signaling molecules, protecting against the development of insulin resistance and the metabolic syndrome. In this project, we conducted experiments to investigate impacts of this nov … More el factor on glucose and lipid metabolism. Adenoviral over-expression of TFE3 strongly activated gene expression of IRS-2, Akt1, Hexokinase II in the liver, leading to amelioration of insulin resistance and reduction in plasma glucose levels in several diabetic models such as db/db, KK-Ay, and diet-induced obesity mice as well as STZ-teated diabetic mice. Regulation of IRS-2 is the primary site where TFE3 in synergy with Foxo1, and SREBP-1c converge. Taken together, TFE3/Foxo1 and SREBP-1c reciprocally regulate IRS-2 expression and insulin sensitivity in the liver. This scenario provides a mechanistic explanation for the physiological link between glucose and lipid metabolism such as physiological switching glycogen synthesis to lipogenesis. In addition, these two transcription factors may ultimately contribute to pathophysiological effects of over-nutrition leading to development of the metabolic syndrome and diabetes. In this review I will discuss roles of SREBP-1c and TFE3 in homeostasis of energy metabolism and in metabolic disturbances, focusing on hepatic insulin sensitivity. Less

参与碳水化合物和脂质代谢的基因在转录水平上以协调的方式进行营养调节。SREBP-1c是一种bHLH转录因子，控制脂肪生成，在营养过度时被诱导，促进葡萄糖转化为脂肪酸和甘油三酯，以储存多余的能量。核SREBP-1c在肝脏中不受控制的激活，由于胰岛素信号通路的直接抑制，可导致肝骨坏死、高甘油三酯血症和肝脏胰岛素抵抗，促进代谢综合征的发展。相反，在试图寻找一种可能对肥胖或胰岛素抵抗相关疾病具有治疗作用的新因子时，我们发现了TFE3，一种新的bHLH转录因子，可激活各种胰岛素信号分子，防止胰岛素抵抗和代谢综合征的发展。在本课题中，我们通过实验研究了该因子对糖脂代谢的影响。腺病毒过表达TFE3强烈激活肝脏中IRS-2、Akt1、己糖激酶II的基因表达，从而改善几种糖尿病模型（如db/db、KK-Ay、饮食诱导的肥胖小鼠以及STZ-teated糖尿病小鼠）的胰岛素抵抗和血浆葡萄糖水平降低。IRS-2的调控是TFE3与Foxo1和SREBP-1c协同作用的主要位点。综上所述，TFE3/Foxo1和SREBP-1c相互调节肝脏中IRS-2的表达和胰岛素敏感性。这种情况为糖脂代谢之间的生理联系提供了一种机制解释，如糖原合成到脂肪生成的生理转换。此外，这两种转录因子可能最终导致营养过剩的病理生理效应，从而导致代谢综合征和糖尿病的发生。在这篇综述中，我将讨论SREBP-1c和TFE3在能量代谢稳态和代谢紊乱中的作用，重点是肝脏胰岛素敏感性。少