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

参与碳水化合物和脂肪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是一种控制脂肪生成的bHLH转录因子，在过度营养时被诱导，以促进葡萄糖转化为脂肪酸和甘油三酯，以储存多余的能量。肝脏核SREBP-1c的失控激活可直接抑制胰岛素信号通路，导致肝脏骨质疏松症、高甘油三酯血症和肝脏胰岛素抵抗，加速代谢综合征的发生。相反，为了寻找对肥胖或胰岛素抵抗相关疾病具有治疗作用的新因子，我们确定了TFE3，一种新的bHLH转录因子，它可以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生。在这个项目中，我们进行了实验来研究这个新的…的影响更多的EL因子对糖脂代谢有影响。腺病毒过表达TFE3可显著激活肝脏中IRS-2、Akt1、己糖激酶II的基因表达，改善糖尿病模型如db/db、KK-Ay、饮食诱导的肥胖小鼠和STZ糖尿病小鼠的胰岛素抵抗和血糖水平。IRS-2的调控是TFE3与Foxo1协同作用和SREBP-1c融合的主要部位。总之，TFE3/Foxo1和SREBP-1c相互调节肝脏中IRS-2的表达和胰岛素敏感性。这一情景为葡萄糖和脂肪代谢之间的生理联系提供了一种机制解释，例如生理上将糖原合成转换为脂肪生成。此外，这两个转录因子可能最终导致过度营养的病理生理效应，导致代谢综合征和糖尿病的发展。在这篇综述中，我将讨论SREBP-1c和TFE3在能量代谢动态平衡和代谢紊乱中的作用，重点是肝脏对胰岛素的敏感性。较少

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