Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling

FoxO 信号传导对代谢和肝脏稳态的转录调节

基本信息

批准号：
9061672
负责人：
Shaodong Guo
金额：
$ 32.3万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061672
关键词：
1-Phosphatidylinositol 3-Kinase Address Alanine Autophagocytosis Biological Process Blood Caenorhabditis elegans Cell physiology Cells Cre-LoxP Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Diabetes Mellitus Diabetic mouse Drosophila genus Endocrine Enzymes FOXO1A gene FOXO3A gene Failure Fasting Functional disorder Gene Expression Genes Genetic Transcription Glucagon Gluconeogenesis Glucose Glycogen HepG2 Hepatic Hepatocyte Homeostasis Hormones Human Hyperglycemia Insulin Insulin Resistance Knockout Mice Link Lipids Liquid substance Liver Liver Failure Longevity Mammals Mass Spectrum Analysis Mediating Mediator of activation protein Metabolic Metabolic Control Metabolism Mitochondria Molecular Mus Mutant Strains Mice Mutate Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Export Organ Organelles Pathway interactions Patients Phospho-Specific Antibodies Phosphorylation Phosphorylation Site Physiological Play Primary carcinoma of the liver cells Protein Dephosphorylation Protein Kinase Proteins Proto-Oncogene Proteins c-akt Regulation Role Second Messenger Systems Signal Pathway Signal Transduction System Therapeutic Intervention Transcriptional Regulation Ubiquitination amino acid metabolism base db/db mouse diabetic disorder control feeding forkhead protein gain of function genetic analysis glucose production glucose-6-phosphatase glycogenolysis improved in vivo insulin receptor substrate 1 protein insulin signaling liver function macromolecule mouse model novel prevent second messenger

项目摘要

DESCRIPTION (provided by applicant): This proposal "Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling" addresses the fundamental mechanism of diabetes by studying fuel hormone's action in the liver. Elevated blood glucagon levels and defective insulin action in patients with type 2 diabetes are responsible for hyperglycemia, but the molecular mechanisms remain elusive. Glucagon and insulin reciprocally control metabolic and cellular homeostasis, in which the liver is a major organ that executes their cellular functions. In the fasting liver, glucagon stimulates gluconeogenesis, degrades macromolecules including glycogen, lipid, and protein, and promotes the autophagic pathway that regulates cellular organelle turnover. In the feeding liver, insulin reverses the catabolic metabolism of glucagon. The metabolic and cellular adaptation from fasting to feeding requires a tight control of gene transcription by opposing effects of the two hormones, and the failure of the adaptation causes hyperglycemia in diabetes. The forkhead transcription factor Foxo1 that regulates multiple biological processes is inhibited by insulin signaling. Insulin phosphorylates Foxo1 at Ser253 in mice or S256 in humans via PKB activation, and triggers Foxo1 nuclear export and cytoplasmic sequestration for ubiquitination. Conversely, glucagon promotes Foxo1 protein stability in the fasting liver or the liver of diabetes when insulin level is decreased or insulin resistance occurs. Foxo1 can mediate the effect of cyclic AMP, the second messenger of glucagon, on expression of gluconeogenic enzymes and autophagic genes, but the role of Foxo1 and its regulation by glucagon, particularly in concert with insulin resistance, in metabolic regulation and cellular function is completely unclear. In Aim 1, we will use Foxo1 liver-specific knockout mice and examine whether Foxo1 is a key mediator in glucagon signaling to regulate hepatic glucose production, glycogenolysis, lipid and protein homeostasis, mitochondrial turnover and function, autophagy and survival, whereas disruption of Foxo1 prevents the glucagon-induced biological processes that promote the development of diabetes. In Aim2, we will use mass-spectrometry and phospho-specific antibodies to determine whether Foxo1 phosphorylation at S153 by glucagon and protein kinase PKA promotes nuclear targeting and whether phosphorylation at S276 enhances transcriptional activity in cells. In Aim 3, we have generated Foxo1- S253A mutant mice mimicking insulin resistance at the Foxo1 level in vivo. Using this unique mouse model, we will determine whether glucagon stimulates the effect of dephosphorylated Foxo1, disrupting metabolic and cellular homeostasis and liver function. In overall, we use Foxo1 gene loss- and gain-of-function approaches to investigate the physiological role of Foxo1 in glucagon action and identify novel molecular mechanisms of Foxo1 activation, which will advance our understanding of the mechanism of diabetes and help develop strategies detecting and inhibiting the glucagon->Foxo1 pathway to control the disease.

描述（由申请人提供）：该提案“ FOXO信号传导对代谢和肝稳态的转录调节”通过研究燃料激素在肝脏中的作用来解决糖尿病的基本机制。 2型糖尿病患者的血糖水平升高和胰岛素作用有缺陷，导致高血糖症，但分子机制仍然难以捉摸。胰高血糖素和胰岛素相互控制的代谢和细胞稳态，其中肝脏是执行其细胞功能的主要器官。在空腹肝脏中，胰高血糖素刺激糖异生，降解在内的大分子，包括糖原，脂质和蛋白质，并促进调节细胞器细胞器周转的自噬途径。在喂养肝脏中，胰岛素逆转胰高血糖素的分解代谢代谢。从禁食到喂养的代谢和细胞适应需要通过两种激素的相反作用来严格控制基因转录，并且适应性的失败会导致糖尿病中高血糖。胰岛素信号传导抑制了调节多种生物过程的叉头转录因子FOXO1。胰岛素通过PKB激活在小鼠或人类中Ser253处的FOXO1磷酸化，并触发FOXO1核出口和细胞质隔离来实现泛素化。相反，胰高血糖素在胰岛素水平降低或发生胰岛素抵抗时促进空腹肝脏或糖尿病肝脏的FOXO1蛋白稳定性。 FOXO1可以介导胰高血糖素第二信使环循环AMP的影响，对葡萄糖生成酶和自噬基因的表达，但是FOXO1的作用及其对胰高血糖素的调节，尤其是与胰岛素抗性的调节，尤其是在代谢中的胰岛素抵抗。调节和细胞功能尚不清楚。在AIM 1中，我们将使用FOXO1肝特异性敲除小鼠，并检查FOXO1是否是胰高血糖素信号的关键介体，以调节肝葡萄糖产生，糖基解体，脂质和蛋白质的稳态，线粒体的跨性别和功能，功能和生存，同时促进了Foxogogon的培训，以至于促进了gllogication to dimogination to intogation to intogation to indodiment to diargogation indodiment to diargogon对葡萄糖的发展。在AIM2中，我们将使用质谱法和磷酸特异性抗体来确定胰高血糖素和蛋白激酶PKA在S153处的FOXO1磷酸化是否会促进核靶向，以及S276的磷酸化是否会增强细胞中的转录活性。在AIM 3中，我们产生了FOXO1-S253A突变小鼠，模仿了体内FOXO1水平的胰岛素耐药性。使用这种独特的小鼠模型，我们将确定胰高血糖素是否刺激去磷酸化的FOXO1的作用，破坏代谢和细胞稳态和肝功能。总体而言，我们使用FOXO1基因丧失和功能获得方法来研究FOXO1在胰高血糖素作用中的生理作用，并鉴定FOXO1激活的新型分子机制，这将提高我们对糖尿病机制的理解，并帮助开发检测和抑制葡萄糖> FOXO1-foxo1控制疾病的策略。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Down-regulation of miR-34a alleviates mesangial proliferation in vitro and glomerular hypertrophy in early diabetic nephropathy mice by targeting GAS1.

DOI：
10.1016/j.jdiacomp.2014.01.002
发表时间：
2014-05
期刊：
Journal of diabetes and its complications
影响因子：
3
作者：
Zhang L;He S;Guo S;Xie W;Xin R;Yu H;Yang F;Qiu J;Zhang D;Zhou S;Zhang K
通讯作者：
Zhang K

Activation of Foxo1 by insulin resistance promotes cardiac dysfunction and β-myosin heavy chain gene expression.

DOI：
10.1161/circheartfailure.114.001457
发表时间：
2015-01
期刊：
CIRCULATION-HEART FAILURE
影响因子：
9.7
作者：
Qi, Yajuan;Zhu, Qinglei;Zhang, Kebin;Thomas, Candice;Wu, Yuxin;Kumar, Rajesh;Baker, Kenneth M.;Xu, Zihui;Chen, Shouwen;Guo, Shaodong
通讯作者：
Guo, Shaodong

Structural and functional analysis of the related transcriptional enhancer factor-1 and NF-κB interaction.

相关转录增强因子-1 和 NF-κB 相互作用的结构和功能分析。

DOI：
10.1152/ajpheart.00069.2013
发表时间：
2014
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Ma,Jieliang;Zhang,Li;Tipton,AaronR;Wu,Jiaping;Messmer-Blust,AngelaF;Philbrick,MelissaJ;Qi,Yajuan;Liu,Song-Tao;Liu,Hongsheng;Li,Jian;Guo,Shaodong
通讯作者：
Guo,Shaodong

Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms.