Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease

非酒精性脂肪肝的脑内质网应激

• 批准号: 10443599
• 负责人: Colin Neal Young
• 金额: $ 48.59万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443599
• 关键词: Acute; Address; Affect; American; Animals; Area; Automobile Driving; Autonomic nervous system; Brain; Carcinoma; Cell Nucleus; Chronic; Collection; Data; Development; Dominant-Negative Mutation; Endoplasmic Reticulum; Enterobacteria phage P1 Cre recombinase; Epidemic; Excision; GRP78 gene; Gene Expression; Gene Transfer; Generations; Health; Hepatic; Histologic; Hypothalamic structure; Image; Incidence; Insulin Resistance; Link; Liver; Maintenance; Mediating; Mediator of activation protein; Metabolic Control; Metabolic Diseases; Molecular; Molecular Chaperones; Mus; Nerve; Nervous System Physiology; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Pathologic; Pathology; Pathway interactions; Peripheral; Phosphorylation; Physiological; Play; Population; Prevention; Prosencephalon; Proteins; Regulation; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Stress; Subfornical Organ; Sympathetic Nervous System; Transcription Factor AP-1; Transcriptional Activation; Transgenic Mice; Triglycerides; Viral Genes; XBP1 gene; arm; base; diet-induced obesity; endoplasmic reticulum stress; global health; in vivo bioluminescence imaging; inducible gene expression; inhibitor; innovation; insight; liver metabolism; molecular imaging; mutant; new therapeutic target; non-alcoholic fatty liver disease; novel; novel strategies; obesity development; obesity prevention; overexpression; paraventricular nucleus; preservation; protein folding; relating to nervous system; response; sensor; spatiotemporal; transcription factor

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.

项目概要： 非酒精性脂肪性肝病（NAFLD）影响三分之一的美国人，是II型的重要风险因素 糖尿病、胰岛素抵抗和肝癌。以肝脏甘油三酯过多为特征 随着NAFLD的累积，NAFLD的发病率呈指数级增加-与日益增长的肥胖流行一致。 越来越多的证据表明，内质网（ER）应激诱导的转录因子激活是 参与NAFLD的产生和维持。而外围层面的机制， 重要的是，自主神经系统的变化知之甚少，但在急性和长期 长期调节肝脏代谢。我们的初步数据已经确定了新的目标， 以及在小鼠饮食诱导的肥胖期间在NAFLD中起重要作用的神经元群体，包括 在前脑和下丘脑区域，涉及ER应激和转录因子的激活 激活蛋白-1（AP-1）。我们还提供了关键证据， 流出到肝脏是驱动NAFLD的潜在成分。利用创新的成像技术， 分子，神经解剖学和综合生理学的方法，我们将解决的中心假设 ER应激诱导的前脑-下丘脑AP-1激活引起的肝交感神经过度活跃 电路在推动NAFLD的发展方面至关重要。我们的新的初步发现强调了ER应激， 前脑穹窿下器和下丘脑室旁核作为饮食过程中NAFLD的介导者- 诱导小鼠肥胖，并指出肝交感神经活动的升高是原因。基础上 这些发现，在目标1中，我们将全面评估前脑和下丘脑内质网应激的作用， 不同的神经元群体在肥胖诱导的肝交感神经过度活跃和NAFLD的发展。 CNS功能的长期改变，包括交感神经系统的慢性激活， 需要通过调节诱导型转录因子来改变基因表达。与此同时，在Aim 2、我们将研究ER应激在下丘脑神经元AP-1激活中的作用， NAFLD的发展。脑AP-1激活在NAFLD病理学中的功能作用也将被进一步研究。 考察研究CNS ER应激与转录因子激活在调控细胞凋亡中的联系， 肝交感神经流出和NAFLD的发展有可能确定新的治疗靶点， 这种情况的治疗和预防。此外，结合活体动物分子成像， 脑部位和神经元亚型特异性操作，直接记录中枢交感神经流出到 肝脏，全面的组织学和分子肝脏分析提供了一种新颖且综合的 了解NAFLD发展的方法。

项目成果

A forebrain-hypothalamic ER stress driven circuit mediates hepatic steatosis during obesity.

• DOI: 10.1016/j.molmet.2023.101858
• 发表时间: 2024-01
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Blackmore, Katherine;Houchen, Claire J.;Simonyan, Hayk;Arestakesyan, Hovhannes;Stark, Alyssa K.;Dow, Samantha A.;Kim, Han Rae;Jeong, Jin Kwon;Popratiloff, Anastas;Young, Colin N.
• 通讯作者: Young, Colin N.

Central Feminization of Obese Male Mice Reduces Metabolic Syndrome.

• DOI: 10.3390/brainsci12101324
• 发表时间: 2022-09-30
• 期刊: BRAIN SCIENCES
• 影响因子: 3.3
• 作者: Blackmore, Katherine;Young, Colin N.
• 通讯作者: Young, Colin N.