Role of TAZ in metabolic regulation in both normal and insulin resistant states

我们的长期目标是确定控制代谢稳态的分子机制，从而确定代谢性疾病的治疗方法。虽然代谢调节对于生物体的功能和存活至关重要，但与胰岛素抵抗相关的代谢失调引起糖尿病、非酒精性脂肪肝、血脂异常和心血管疾病。本项目的目的是确定肝脏TAZ（具有PDZ结合基序的转录辅激活因子）在正常和胰岛素抵抗状态下调节糖和脂质代谢中的作用。调节细胞生长的蛋白质与控制代谢稳态的蛋白质重叠。因此，我们确定是否TAZ，这是已知的控制增殖，调节肝脏代谢。利用分子、生物化学和遗传学方法，我们获得了初步数据，表明TAZ独立于Hippo通路，是肝脏能量稳态的独特调节剂。肝脏TAZ蛋白通过禁食和进食而动态改变，并且TAZ调节响应禁食和进食的致炎基因和脂肪生成基因的差异表达。然而，在胰岛素抵抗状态下，TAZ的失调导致葡萄糖和脂质稳态的扰动。在此基础上，我们提出了一系列的分子和小鼠研究来描述肝TAZ调节生理和病理胰岛素抵抗状态下葡萄糖和脂质代谢的分子机制。我们的目标如下。具体目标1是确定肝脏TAZ在致瘤基因表达和葡萄糖稳态调节中的作用。具体目标2是确定肝脏TAZ在从头脂肪生成基因表达和甘油三酯稳态调节中的作用。我们期望我们的研究将确定TAZ在代谢调节中的新作用，并确定葡萄糖和脂质稳态生理调节的分子机制。我们还期望我们的研究将提供对胰岛素抵抗的发病机制的机制见解，从而能够开发胰岛素抵抗相关代谢疾病的治疗方法，包括糖尿病，脂肪肝，血脂异常和心血管疾病。

Our long-term goal is to determine the molecular mechanisms that control metabolic homeostasis and there by identify therapies for metabolic diseases. While metabolic regulation is vital for an organism’s function and survival, metabolic dysregulation associated with insulin resistance gives rise to diabetes, non-alcoholic fatty liver disease, dyslipidemia, and cardiovascular disease. The goal of this project is to define the role of hepatic TAZ (transcriptional co-activator with PDZ binding motif) in the regulation of glucose and lipid metabolism in normal and insulin resistant states. Proteins that regulate cell growth overlap with those that control metabolic homeostasis. Therefore, we determined whether TAZ, which is known to control proliferation, regulates hepatic metabolism. Using molecular, biochemical, and genetic approaches, we obtained preliminary data which reveal that TAZ, independent of the Hippo pathway, is a unique regulator of energy homeostasis in the liver. Hepatic TAZ protein is dynamically altered by fasting and feeding, and TAZ regulates the differential expression of gluconeogenic and lipogenic genes in response to fasting and feeding. However, in insulin resistant states, the dysregulation of TAZ leads to perturbations of both glucose and lipid homeostasis. To build on this preliminary work, we propose a series of molecular and mouse studies to delineate the molecular mechanisms whereby hepatic TAZ regulates glucose and lipid metabolism in physiologic and pathologic insulin resistant states. Our aims are listed below. Specific Aim 1 is to define the role of hepatic TAZ in the regulation of gluconeogenic gene expression and glucose homeostasis. Specific Aim 2 is to define the role of hepatic TAZ in the regulation of de novo lipogenic gene expression and triglyceride homeostasis. We expect that our studies will define a new role for TAZ in metabolic regulation and will identify molecular mechanisms whereby glucose and lipid homeostasis are physiologically regulated. We also expect that our studies will provide mechanistic insights into the pathogenesis of insulin resistance, and thereby enable the development of therapies for insulin resistance-associated metabolic diseases, including diabetes, hepatosteatosis, dyslipidemia, and cardiovascular disease.