SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling
SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling
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DOI：
10.1007/s00109-007-0158-5
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发表时间：
2007-02
期刊：
影响因子：
--
通讯作者：
H. Shimano
中科院分区：
文献类型：
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作者：
H. Shimano
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bHLH转录因子，控制脂肪生成，在营养过剩时被诱导，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，TFE3是一种新的bHLH转录因子，能强烈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。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。这一情景为糖和脂肪代谢之间的生理联系提供了一种机制解释，例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，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。
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 controls lipogenesis and is induced during overnutrition 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, TFE3 is a novel bHLH transcription factor that strongly activates various insulin signaling molecules, protecting against the development of insulin resistance and the metabolic syndrome. 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 of glycogen synthesis to lipogenesis. In addition, these two transcription factors may ultimately contribute to pathophysiological effects of overnutrition leading to the 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.