The Role of Leptin in Liver Fibrogenesis

瘦素在肝纤维形成中的作用

• 批准号: 7600655
• 负责人: FRANK A ANANIA
• 金额: $ 32.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600655
• 关键词: Accounting; Adenosine; Adipose tissue; American; Apoptosis; Biological; Body mass index; Carbon Tetrachloride; Cause of Death; Cell Proliferation; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical; Collagen; Collagen Type I; Cryptogenic cirrhosis; Data; Development; Disease; Disease Progression; Etiology; Extracellular Matrix; Female; Fibrosis; Funding; Genes; Genetic Transcription; Goals; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatocyte; Hormones; Human; Hypertriglyceridemia; In Vitro; Inflammation; Injection of therapeutic agent; Insulin Resistance; Janus kinase 2; Knock-out; Knockout Mice; Laboratories; Lead; Leptin; Liver; Liver Fibrosis; Liver diseases; MAPK14 gene; Matrix Metalloproteinases; Messenger RNA; Metabolic syndrome; Mission; Molecular; Mono-S; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Production; Progress Reports; Rattus; Research; Rodent; Role; STAT protein; Signal Transduction; Signal Transduction Pathway; Staining method; Stains; Testing; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Tissues; Transcriptional Activation; United States; United States National Center for Health Statistics; Wound Healing; adiponectin; base; collagenase 3; cytokine; design; diabetic; extracellular; in vivo; inorganic phosphate; lipid metabolism; male; meetings; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; public health relevance

DESCRIPTION (provided by applicant): Cirrhosis is the tenth leading cause of deaths in the United States in males and the twelfth leading cause of death in females. Non-alcoholic fatty liver disease (NAFLD) may account for the majority of patients who have cryptogenic cirrhosis. The majority of cases of NAFLD are related to metabolic syndrome which includes obesity, type 2 diabetes mellitus, and hypertriglyceridemia. According to retrospective data approximately 3% of the American people have NASH (non-alcoholic steatohepatitis). Our long-term consequence of disease progression to cirrhosis will impose great challenges to the American people. The long-term goal is to elucidate the molecular basis for liver fibrosis, which can ultimately lead to cirrhosis. This proposal meets the mission of the action plan for liver disease research. In the prior funding period, we have convincingly demonstrated that leptin, an adipocytokine produced primarily by white adipose tissue, is a profibrogenic cytokine in the development of hepatic fibrosis. Leptin augments net production of extracellular matrix (ECM) by increasing hepatic stellate cell proliferation (HSC), increases type I collagen synthesis and increases tissue inhibitor of metalloproteinase 1 (TIMP-1); and impedes a timely death of HSCs by strongly inhibiting apoptosis. The overall goal of the current proposal is to demonstrate the biological consequences of leptin and adiponectin as novel modulators of liver fibrosis. We hypothesize that adiponectin is protective against leptin-induced hepatic fibrosis in vitro and in vivo by AMPK blockade of Jak2/Stat3 signal transduction. Three specific aims have been designed to test this hypothesis. (1). To dissect the molecular pathway whereby adiponectin-activated AMPK impedes Jak2/Stat3 signal transduction, and determine whether leptin enhanced signaling via the PI-3K/Akt and extracellular regulated kinase (Erk, p44/p42), and p38 pathways are directly inhibited as assessed by HSC proliferation and apoptosis.(2).To demonstrate that adiponectin antagonizes leptin's action in the rat HSC by reducing net production of extracellular matrix (ECM) molecules, decreasing the transcriptional activity of tissue inhibitor of metalloproteinase I (TIMP-1) and increasing the functional activity of matrix metalloproteinases (MMPs) that are known to degrade type I collagen. (3). To employ adiponectin knockout (Ad KO) mice to elucidate in vivo how adiponectin modulates the biological effect of leptin in hepatic fibrogenesis as assessed by carbon tetrachloride (CCl4) exposure. PUBLIC HEALTH RELEVANCE: Cirrhosis is a major cause of death in the United States. A primary focus of the laboratory is to unlock molecular switches that regulate the scar tissue known to cause this chronic liver disease. We have observed that two hormones associated with fat metabolism -leptin and adiponectin- can alter the dynamics of scar formation in the liver as well as in the hepatic cells associated with this disease in humans. The project seeks to determine whether adiponectin can act as a protector from the harmful effects of leptin in liver fibrosis.

描述（由申请人提供）：肝硬化是美国男性第十大死亡原因，女性第十二大死亡原因。非酒精性脂肪性肝病（NAFLD）可能是大多数隐源性肝硬化患者的原因。大多数NAFLD病例与代谢综合征有关，包括肥胖、2型糖尿病和高脂血症。根据回顾性数据，大约3%的美国人患有NASH（非酒精性脂肪性肝炎）。我们疾病进展为肝硬化的长期后果将给美国人民带来巨大挑战。长期的目标是阐明肝纤维化的分子基础，最终导致肝硬化。该提案符合肝病研究行动计划的使命。在之前的资助期间，我们已经令人信服地证明了瘦素，一种主要由白色脂肪组织产生的脂肪细胞因子，是肝纤维化发展中的促纤维化细胞因子。瘦素通过增加肝星状细胞增殖（HSC）来增加细胞外基质（ECM）的净产生，增加I型胶原合成并增加金属蛋白酶组织抑制剂1（TIMP-1）;并通过强烈抑制细胞凋亡来阻止HSC的适时死亡。目前的建议的总体目标是证明瘦素和脂联素作为新的肝纤维化调节剂的生物学后果。我们假设脂联素通过AMPK阻断Jak 2/Stat 3信号转导，在体外和体内对瘦素诱导的肝纤维化具有保护作用。为了检验这一假设，设计了三个具体目标。（一）.分析脂联素激活的AMPK阻碍Jak 2/Stat 3信号转导的分子途径，并通过评估HSC增殖和凋亡来确定瘦素是否通过PI-3 K/Akt和细胞外调节激酶（Erk，p44/p42）以及p38途径直接抑制信号转导。（2）脂联素通过减少细胞外基质（ECM）分子的净产生、降低金属蛋白酶组织抑制因子I（TIMP-1）的转录活性和增加已知降解I型胶原的基质金属蛋白酶（MMPs）的功能活性来拮抗瘦素在大鼠HSC中的作用。（三）、采用脂联素基因敲除（Ad KO）小鼠，在体内阐明脂联素如何调节瘦素在四氯化碳（CCl 4）暴露评估的肝纤维化中的生物学效应。公共卫生相关性：肝硬化是美国的主要死亡原因。该实验室的一个主要重点是解开分子开关，调节已知导致这种慢性肝病的疤痕组织。我们已经观察到，与脂肪代谢相关的两种激素-瘦素和脂联素-可以改变肝脏以及与人类这种疾病相关的肝细胞中瘢痕形成的动力学。该项目旨在确定脂联素是否可以作为瘦素在肝纤维化中的有害作用的保护剂。