Regulation of Hepatic Steatosis by an ER Stress-Inducible Transcription Factor CR

内质网应激诱导转录因子 CR 对肝脂肪变性的调节

• 批准号: 8023261
• 负责人: Kezhong Zhang
• 金额: $ 38万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8023261
• 关键词: Acute; Address; Applications Grants; Automobile Driving; Bioinformatics; CCAAT-Enhancer-Binding Protein-beta; Cardiovascular Diseases; Cessation of life; Chronic; 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; Regulation; 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; 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; response; transcription factor

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）的关键代谢前体，这是美国肝相关疾病和死亡的主要原因。当前，NAFLD中的疾病进展是由对肝脂肪变性施加的急性侮辱（“第二击”）触发的（“第一次命中”）。然而，对“两个命中”触发从可逆脂肪变性到nafld的过渡的分子基础的精确理解仍然难以捉摸。以前，我们揭示了一种新型的肝特异性转录因子CREBH（环状响应 - 元素结合蛋白H），该蛋白质被内质网应激（ER）激活，以介导肝脏中的急性相相炎症反应。最近，我们积累了强有力的初步证据，即CREBH在代谢应激条件下调节肝脂质稳态中起着至关重要的作用。饱和脂肪酸，炎性刺激或高脂喂养可以在体外或体内诱导CREBH的裂解，从而导致其激活。小鼠中CREBH的缺失导致关键脂肪生成酶的表达降低，并响应急性ER胁迫或动脉粥样硬化的高脂喂养而减少肝脂质积累。高脂喂养6个月后，与对照小鼠相比，CREBH无效小鼠的肝脂肪变性和炎症明显较小，但胰岛素敏感性和葡萄糖耐受性更高。此外，发现CREBH激活了关键脂肪生成调节剂的表达，包括CCAAT-增强剂结合蛋白β（C/EBP2）和过氧化物酶体增殖物激活的受体伽马（PPAR3），在代谢胁迫下在肝脏肝细胞中。这些观察结果导致了该提议的中心假设：由过度饱和脂肪酸或促炎性细胞因子引起的代谢应激激活CREBH；然后，激活的CrebH充当脂肪生成转录调节剂，以传播肝脂肪变性和脂肪性肝炎。在此赠款应用中，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特定目的：（1）描述代谢因素（包括饱和脂肪酸和促炎性细胞因子）的调节机制激活CREBH； （2）在调节肝脂质稳态时，在调节CrebH介导的应力信号传导的分子基础上； （3）确定CrebH在代谢应激下肝脂肪变性向脂肪性肝炎的过渡中的作用。这项工作代表了阐明肝脂肪变性和脂肪性肝炎中与ER应力相关机制的一种新型途径，目前知之甚少。拟议研究的完成不仅将定义分子基础，通过这种分子基础，新型应激诱导的转录因子调节肝脂质代谢，而且对于为预防和治疗人NAFLD及其相关的代谢综合症设计新的策略也很重要。 公共卫生相关性：非酒精性脂肪肝疾病（NAFLD），是肝相关疾病和死亡的主要原因，经常在肥胖症，II型糖尿病和心血管疾病之前或共存。该项目将确定新型应激诱导转录因子CREBH促进脂肪肝和NAFLD在代谢应激下的进展的调节机制。了解肝脂质积累中应力诱导的分子机制及其相关的发病机理是开发针对NAFLD的新诊断和治疗剂的关键先决条件。