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性肝病（NAFLD）的关键代谢前体，NAFLD是美国肝脏相关疾病和死亡的主要原因。目前认为，NAFLD的疾病进展是由肝脏脂肪变性（“第一次发作”）造成的急性损伤（“第二次发作”）引发的。然而，对“两击”触发从可逆脂肪变性到NAFLD转变的分子基础的精确理解仍然难以捉摸。之前，我们发现了一种新的肝脏特异性转录因子CREBH（循环amp -反应元件结合蛋白H），它被内质网（ER）应激激活，介导肝脏急性期炎症反应。最近，我们已经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脏脂质稳态中起着至关重要的作用。饱和脂肪酸、炎症刺激或高脂肪喂养可诱导体外或体内CREBH的裂解，导致其活化。小鼠中CREBH的缺失导致关键脂肪生成酶的表达降低，并减少肝脏脂质积累，以应对急性内质网应激或致动脉粥样硬化的高脂肪喂养。高脂喂养6个月后，与对照组小鼠相比，CREBH小鼠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，研究发现CREBH可激活代谢应激下肝细胞中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)等关键脂肪生成调节因子的表达。这些观察结果导致了该提议的中心假设：代谢应激，由过多的饱和脂肪酸或促炎细胞因子引起，激活CREBH；然后，激活的CREBH作为脂肪生成转录调节因子，传播肝脂肪变性和脂肪性肝炎。在本次申请中，我们将阐明CREBH在调节肝脏脂肪变性和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)描述代谢因子，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介导的应激信号在调节肝脏脂质稳态中的分子基础；(3)确定代谢应激下CREBH在肝脏脂肪变性向脂肪性肝炎转变中的作用。这项工作代表了一个新的途径来阐明内质网应激相关的机制在肝脂肪变性和脂肪性肝炎目前知之甚少。上述研究的完成不仅将确定一种新的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。