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，并通过确定代谢疾病的治疗方法。虽然代谢调节对生物体的功能和生存至关重要，但与胰岛素抵抗相关的代谢失调会导致糖尿病、非酒精性脂肪性肝病、血脂异常和心血管疾病。本项目的目标是确定TAZ（带PDZ结合基序的转录共激活因子）在正常和胰岛素抵抗状态下调节葡萄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，我们确定已知控制增殖的TAZ是否调节肝脏代谢。利用分子、生化和遗传方法，我们获得的初步数据表明，TAZ独立于Hippo通路，是肝脏能量稳态的独特调节剂。禁食和摄食会动态改变肝脏TAZ蛋白，TAZ调节糖异生和脂肪生成基因在禁食和摄食条件下的差异表达。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。在这一初步工作的基础上，我们提出了一系列的分子和小鼠研究，以描述在生理性和病理性胰岛素抵抗状态下肝脏TAZ调节葡萄糖和脂质代谢的分子机制。我们的目标如下。具体目的1是确定肝TAZ在糖异生基因表达和葡萄糖稳态调节中的作用。具体目的2是确定肝脏TAZ在调节新生脂肪基因表达和甘油三酯稳态中的作用。我们期望我们的研究将确定TAZ在代谢调节中的新作用，并将确定葡萄糖和脂质稳态生理调节的分子机制。我们也期望我们的研究将为胰岛素抵抗的发病机制提供深入的见解，从而促进胰岛素抵抗相关代谢疾病的治疗，包括糖尿病、肝纤维化、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.