Hepatic Steatosis and ER Stress-Inducible Transcription Factor CREBH

肝脂肪变性与内质网应激诱导转录因子 CREBH

基本信息

批准号：
8209093
负责人：
Kezhong Zhang
金额：
$ 33.06万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209093
关键词：
Acute Address Applications Grants Automobile Driving Bioinformatics CCAAT-Enhancer-Binding Protein-beta Cardiovascular Diseases Cessation of life Cirrhosis Cyclic AMP-Responsive DNA-Binding Protein Development Diet Disease Progression Disease model Endoplasmic Reticulum Enzymes Event Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Funding Future Genes Goals Hepatic Hepatitis Hepatocyte Homeostasis Human In Vitro Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Lead Lipids Liver Liver diseases Mediating Metabolic Metabolic stress Metabolic syndrome Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity PPAR gamma Pathogenesis Phase Play Prevention strategy Regulatory Pathway Research Role Saturated Fatty Acids Signal Transduction Staging Steatohepatitis Stimulus Stress Testing Therapeutic Intervention Trans-Activators United States Up-Regulation Work base chromatin immunoprecipitation chronic liver disease cytokine design endoplasmic reticulum stress feeding glucose tolerance in vivo insight insulin sensitivity lipid biosynthesis lipid metabolism loss of function new therapeutic target non-alcoholic fatty liver nonalcoholic steatohepatitis novel novel diagnostics public health relevance response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hepatic steatosis or fatty liver is considered the key metabolic precursor to non-alcoholic fatty liver disease (NAFLD), the major cause of liver-associated illness and death in the United States. Disease progression in NAFLD is currently thought to be triggered by an acute insult (the "second hit") that is imposed on hepatic steatosis (the "first hit"). However, a precise understanding of the molecular basis by which the "two hits" trigger the transition from reversible steatosis to NAFLD remains elusive. Previously, we revealed a novel liver- specific transcription factor CREBH (cyclic-AMP-response-element-binding protein H), which is activated by endoplasmic reticulum (ER) stress to mediate an acute-phase inflammatory response in the liver. Recently, we have accumulated strong preliminary evidence that CREBH plays a crucial role in regulating hepatic lipid homeostasis under metabolic stress conditions. Saturated fatty acids, inflammatory stimuli, or high-fat feeding can induce cleavage of CREBH in vitro or in vivo, leading to its activation. Deletion of CREBH in mice resulted in decreased expression of key lipogenic enzymes and reduced hepatic lipid accumulation in response to acute ER stress or atherogenic high-fat feeding. After the high-fat feeding for 6 months, CREBH null mice displayed significantly less hepatic steatosis and inflammation but greater insulin sensitivity and glucose tolerance, compared to the control mice. Furthermore, CREBH was found to activate expression of key lipogenic regulators, including CCAAT-enhancer-binding protein beta (C/EBP2) and peroxisome proliferator- activated receptor gamma (PPAR3), in liver hepatocytes under the metabolic stress. These observations lead to the central hypothesis of this proposal: metabolic stress, induced by excessive saturated fatty acids or pro- inflammatory cytokines, activates CREBH; activated CREBH then functions as a lipogenic transcriptional regulator to propagate hepatic steatosis and steatohepatitis. In this grant application, we will elucidate the pathophysiologic role and molecular mechanism of CREBH in regulating hepatic steatosis and the development of NAFLD. To achieve our research goal, we will pursue three complementary specific aims: (1) to delineate the regulatory mechanism by which metabolic factors, including saturated fatty acids and pro- inflammatory cytokines, activate CREBH; (2) to decipher the molecular basis of CREBH-mediated stress signaling in regulating hepatic lipid homeostasis; (3) to determine the role of CREBH in the transition of hepatic steatosis to steatohepatitis under the metabolic stress. This work represents a novel avenue to elucidate ER stress-associated mechanisms in hepatic steatosis and steatohepatitis that are currently poorly understood. Completion of the proposed studies will not only define the molecular basis by which a novel, stress-induced transcription factor regulates hepatic lipid metabolism, but will also be significant for designing new strategies for the prevention and treatment of human NAFLD and its associated metabolic syndromes. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD), the major cause of liver-associated illness and deaths, frequently precedes or co-exists with obesity, type II diabetes, and cardiovascular disease. This project will identify the regulatory mechanisms by which a novel stress-inducible transcription factor CREBH promotes fatty liver and progression of NAFLD under metabolic stress. Understanding the stress-induced molecular mechanisms in hepatic lipid accumulation and its associated pathogenesis is a key prerequisite for the development of new diagnostics and therapeutics targeting NAFLD.

描述（由申请人提供）：肝脏脂肪变性或脂肪肝被认为是非酒精性脂肪肝病 (NAFLD) 的关键代谢前兆，是美国肝脏相关疾病和死亡的主要原因。目前认为 NAFLD 的疾病进展是由对肝脂肪变性（“第一次打击”）施加的急性损伤（“第二次打击”）引发的。然而，对于“两次打击”触发从可逆性脂肪变性向 NAFLD 转变的分子基础的精确理解仍然难以捉摸。此前，我们揭示了一种新型肝脏特异性转录因子CREBH（环AMP反应元件结合蛋白H），它被内质网（ER）应激激活，介导肝脏的急性期炎症反应。最近，我们积累了强有力的初步证据，表明 CREBH 在代谢应激条件下调节肝脂质稳态中发挥着至关重要的作用。饱和脂肪酸、炎症刺激或高脂肪喂养可在体外或体内诱导 CREBH 裂解，导致其激活。小鼠体内 CREBH 的缺失导致关键脂肪生成酶的表达减少，并减少了响应急性内质网应激或致动脉粥样化高脂肪喂养的肝脏脂质积累。高脂肪喂养 6 个月后，与对照小鼠相比，CREBH 缺失小鼠的肝脏脂肪变性和炎症明显减少，但胰岛素敏感性和葡萄糖耐量更高。此外，发现 CREBH 在代谢应激下的肝细胞中激活关键脂肪生成调节因子的表达，包括 CCAAT 增强子结合蛋白 β (C/EBP2) 和过氧化物酶体增殖物激活受体 γ (PPAR3)。这些观察结果引出了该提议的中心假设：过量饱和脂肪酸或促炎细胞因子诱导的代谢应激会激活 CREBH；激活的 CREBH 然后作为脂肪生成转录调节因子发挥作用，传播肝脂肪变性和脂肪性肝炎。在本次资助申请中，我们将阐明CREBH在调节肝脂肪变性和NAFLD发展中的病理生理作用和分子机制。为了实现我们的研究目标，我们将追求三个互补的具体目标：（1）描绘代谢因子（包括饱和脂肪酸和促炎细胞因子）激活CREBH的调节机制； (2) 破译CREBH介导的应激信号调节肝脂质稳态的分子基础； (3)确定CREBH在代谢应激下肝脂肪变性向脂肪性肝炎转变中的作用。这项工作代表了阐明目前知之甚少的肝脂肪变性和脂肪性肝炎中内质网应激相关机制的新途径。完成拟议的研究不仅将确定新型应激诱导转录因子调节肝脏脂质代谢的分子基础，而且对于设计预防和治疗人类 NAFLD 及其相关代谢综合征的新策略也具有重要意义。公共卫生相关性：非酒精性脂肪肝病 (NAFLD) 是肝脏相关疾病和死亡的主要原因，经常先于肥胖、II 型糖尿病和心血管疾病发生或同时发生。该项目将确定新型应激诱导转录因子 CREBH 在代谢应激下促进脂肪肝和 NAFLD 进展的调节机制。了解应激诱导的肝脏脂质积累分子机制及其相关发病机制是开发针对 NAFLD 的新诊断和治疗方法的关键先决条件。