Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease

项目总结： 非酒精性脂肪性肝病(NAFLD)影响着三分之一的美国人，是II型的重要危险因素 糖尿病、胰岛素抵抗和肝癌。以肝甘油三酯过多为特征 随着肥胖症的流行，NAFLD的发病率呈指数级增长。 越来越多的证据表明，内质网(ER)应激诱导的转录因子激活 参与NAFLD的产生和维护。而外围设备级别的机制是 重要的是，对自主神经系统的变化知之甚少，但在急性和长期... 肝脏代谢的长期调节。我们的初步数据已经确定了新的靶点、作用机制 以及在饮食诱导的小鼠肥胖过程中在NAFLD中发挥关键作用的神经元群体，包括 在前脑和下丘脑区域，参与内质网应激和转录因子的激活 激活蛋白-1(AP-1)。我们还提供了交感神经系统升高的关键证据 外流到肝脏是导致NAFLD的一个潜在成分。使用创新成像的组合， 分子、神经解剖学和综合生理学方法，我们将讨论中心假说 内质网应激诱导前脑-下丘脑AP-1激活所致的肝脏交感神经过度活动 电路是推动NAFLD发展的关键。我们新的初步发现强调了内质网应激在 饮食中前脑穹隆下器和下丘脑室旁核在NAFLD发病中的作用 诱导小鼠肥胖，并指出肝脏交感神经活性升高是原因之一。建立在 这些发现，在目标1中，我们将综合评估前脑和下丘脑内质网应激在 肥胖诱导的肝脏交感神经过度活动和NAFLD发展中不同的神经细胞群。 中枢神经系统功能的长期变化，包括交感神经系统的慢性激活， 需要通过调节可诱导转录因子来改变基因表达。与此相一致，对准 2，我们将研究内质网应激在下丘脑神经元AP-1激活中的作用。 非酒精性脂肪肝的发展。脑AP-1激活在NAFLD病理中的功能作用也将是 检查过了。中枢神经内质网应激与转录因子激活之间的关系 肝交感神经流出和NAFLD的发展有可能确定新的治疗靶点 对这种情况的治疗和预防。此外，结合活体动物分子成像， 大脑部位和神经元亚型特定的操作，直接记录中枢交感神经流出到 肝脏，以及全面的组织学和分子肝脏分析提供了一种新的和综合的 了解NAFLD发展的方法。

PROJECT SUMMARY: Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized by excessive hepatic triglyceride accumulation, the incidence of NAFLD is increasing exponentially - in line with the growing obesity epidemic. There is mounting evidence that endoplasmic reticulum (ER) stress-induced transcription factor activation is involved in the generation and maintenance of NAFLD. While mechanisms at the peripheral level are important, changes in the autonomic nervous system are poorly understood yet crucial in the acute and long- term regulation of liver metabolism. Our preliminary data have identified novel targets, mechanisms of action and neuronal populations that play an essential role in NAFLD during diet-induced obesity in mice, including within forebrain and hypothalamic regions, involving ER stress and activation of the transcription factor activator protein-1 (AP-1). We also provide key evidence that elevations in sympathetic nervous system outflow to the liver is an underlying component driving NAFLD. Using a combination of innovative imaging, molecular, neuroanatomical and integrative physiological approaches, we will address the central hypothesis that hepatic sympathetic overactivity due to ER stress-induced AP-1 activation in forebrain-hypothalamic circuits is critical in driving the development of NAFLD. Our novel preliminary findings highlight ER stress in the forebrain subfornical organ and hypothalamic paraventricular nucleus as a mediator of NAFLD during diet- induced obesity in mice, and point to elevations in hepatic sympathetic nerve activity as a cause. Building upon these findings, in Aim 1 we will comprehensively evaluate the role of forebrain and hypothalamic ER stress in distinct neuronal populations in obesity-induced hepatic sympathetic overactivity and NAFLD development. Long-lasting alterations in CNS function, including chronic activation of the sympathetic nervous system, require changes in gene expression through regulation of inducible transcription factors. In line with this, in Aim 2, we will examine the role of ER stress in the activation of AP-1 in hypothalamic neurons during the development of NAFLD. The functional role of brain AP-1 activation in the pathology of NAFLD will also be examined. Dissecting the links between CNS ER stress and transcription factor activation in the control of hepatic sympathetic outflow and NAFLD development has the potential to identify new therapeutic targets for the treatment and prevention of this condition. Moreover, the combination of live animal molecular imaging, brain site- and neuron subtype- specific manipulations, direct recording of central sympathetic outflow to the liver, and comprehensive histological and molecular hepatic analysis provides a novel and integrative approach to gain insight into NAFLD development.