Pannexin 1 channels in diet-induced metabolic syndrome

Pannexin 1 通道在饮食诱导的代谢综合征中的作用

基本信息

批准号：
10200124
负责人：
NORBERT LEITINGER
金额：
$ 40.58万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200124
关键词：
Ablation Address Affect Age Aging Antisense Oligonucleotides Atherosclerosis Automobile Driving Blood Vessels CETP gene Cardiometabolic Disease Cardiovascular Diseases Caspase Cells Cellular Metabolic Process Cholesterol Cirrhosis Coculture Techniques Collaborations Data Diabetes Mellitus Diet Disease Disease Progression Elderly Fatty Liver Fibrosis Fructose Genetic Goals Health Hepatic Hepatic Stellate Cell Hepatocyte Hybrids Inbred Strains Mice Incidence Individual Inflammation Knowledge Life Style Liver Liver Fibrosis Liver diseases Mediating Metabolic Metabolic syndrome Metabolism Modality Modeling Molecular Mus Obesity Palmitates Pathologic Pathology Pattern Pharmacology Physiology Play Primary carcinoma of the liver cells Progressive Disease Property Resort Risk Risk Factors Role Signal Transduction Steatohepatitis Syndrome Testing Therapeutic Transgenic Mice Transgenic Organisms United States Virus age related atherosclerosis risk autocrine base blood glucose regulation blood lipid cardiometabolism cardiovascular effects cardiovascular risk factor combat coronary fibrosis extracellular gain of function humanized mouse liver transplantation mouse model mutant non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics overexpression paracrine patient subsets physical inactivity prevent stellate cell synergism western diet

项目摘要

PROJECT 3 PROJECT SUMMARY Lack of physical activity along with a western diet and lifestyle is accompanied by an increased incidence of obesity, diabetes, and fatty liver disease (NAFLD). NAFLD is considered an independent risk factor for cardiovascular disease and encompasses multiple progressive disease conditions beginning with hepatic steatosis, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis, which is also associated with aging and increased risk for cirrhosis and hepatocellular carcinoma. The progression of NAFLD with accompanying hepatic fibrosis poses a significant health problem, culminating in liver transplant as the last resort. Treatment options are limited and there is a tremendous need for novel therapeutic concepts. The mechanisms driving NAFLD progression to fibrosis are largely unknown and may involve multiple insults by cell-derived danger- associated molecular patterns (DAMPs) such as extracellular ATP and its metabolites, which were implied to regulate hepatic inflammation and fibrosis. However, the mechanisms that control the release of ATP from hepatocytes are not known. Our preliminary data demonstrate that hepatocytes express functional pannexin-1 (Panx1) channels that release ATP upon lipotoxicity-induced caspase-dependent cleavage. Pharmacological inhibition or genetic deletion of Panx1 in hepatocytes protected mice against diet- and aging-induced steatosis, steatohepatitis and hepatic fibrosis. Based on these data, we will examine the hypothesis that Panx1- dependent ATP release from hepatocytes promotes fibrosis via activation of stellate cells and we will test if inhibition of Panx1 channel function is a feasible therapeutic approach to combat NASH. In specific Aim 1 we will investigate the effect of hepatic Panx1 deficiency (Panx1fl/fl/Albcre) and virus (AAV8)- mediated Panx1 ablation during the pathologically defined stages of fatty liver disease - steatosis, NASH, and advanced fibrosis, using mice fed a high fructose, palmitate, cholesterol (FPC) diet for 5, 12 or 16 weeks. Virus-mediated hepatic re-expression of Panx1 in Panx1-deficient mice and transgenic overexpression of Panx1 will be used as gain-of-function approaches. We will develop novel liver-specific antisense oligonucleotide (ASO)-mediated therapeutic approaches directed at Panx1, which will be tested in the FPC diet model, in transgenic APOE3- Leiden/CETP mice, a “humanized” mouse model of metabolic syndrome, and in aging-induced fibrosis. In specific Aim 2 we will test the hypotheses that (a) Panx1-dependent ATP release from hepatocytes regulates fibrotic capacity of hepatic stellate cells via paracrine effects, and (b) ATP or its metabolites controls metabolism of hepatocytes via Panx1-dependent autocrine mechanisms. Collectively, these data will provide us new information on diet-induced metabolic complications that are now considered predisposing and accelerating factors, part of the cardiometabolic syndrome; also, our new knowledge on liver fibrosis will also have implications for cardiac fibrosis.

项目3项目摘要缺乏体育锻炼以及西方饮食和生活方式是通过增加的发生率而实现的肥胖，糖尿病和脂肪肝病（NAFLD）。 NAFLD被认为是独立的风险因素心血管疾病，包括从肝的多种进行性疾病状况脂肪变性，非酒精性脂肪性肝炎（NASH）和肝纤维化，这也与衰老和衰老有关肝硬化和肝细胞癌的风险增加。随着参与的NAFLD的发展肝纤维化构成了一个重大的健康问题，最终是肝移植作为最后的手段。治疗选项有限，并且非常需要新型的热概念。驾驶机制 NAFLD向纤维化的进展在很大程度上是未知的，可能涉及细胞衍生的危险 - 相关的分子模式（湿），例如细胞外ATP及其代谢产物，暗示为调节肝注射和纤维化。但是，控制ATP从肝细胞尚不清楚。我们的初步数据表明肝细胞表达功能性pannexin-1 （PANX1）在脂肪毒性诱导的caspase依赖性裂解上释放ATP的通道。药理 PANX1在肝细胞中抑制或遗传缺失保护小鼠免受饮食和衰老诱导的脂肪变性的影响，脂肪性肝炎和肝纤维化。基于这些数据，我们将研究以下假设。依赖性ATP从肝细胞中释放出通过星状细胞的激活促进纤维化，我们将测试是否是否 PANX1通道功能的抑制是对抗NASH的可行治疗方法。在特定的目标1中我们将研究Hepatitic Panx1缺乏症（PANX1FL/FL/ALBCRE）和病毒（AAV8） - 介导的PANX1的影响脂肪肝病的病理定义阶段的消融 - 脂肪变性，纳什和晚期纤维化，使用喂养高果糖，棕榈酸酯，胆固醇（FPC）饮食的小鼠进行5、12或16周。病毒介导 PANX1缺乏小鼠中PANX1的肝脏重新表达将使用PANX1的转基因过表达作为功能收益的方法。我们将开发新型的肝脏特异性反义寡核苷酸（ASO）介导的针对PANX1的治疗方法（将在FPC饮食模型中进行测试）在转基因APOE3-中 Leiden/CETP小鼠，一种代谢综合征的“人性化”小鼠模型，在衰老诱导的纤维化中。在具体目的2我们将测试（a）依赖于肝细胞的PANX1依赖性ATP的假设通过旁分泌作用的肝星状细胞的纤维化能力，（b）ATP或其代谢物控制通过PANX1依赖性自分泌机制的肝细胞代谢。总的来说，这些数据将提供美国有关饮食引起的代谢并发症的新信息，这些信息现在被视为易感性和加速因子，心脏代谢综合征的一部分；此外，我们关于肝纤维化的新知识也将对心脏纤维化有影响。