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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：
10625332
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/10625332
关键词：
Ablation Acceleration Address Affect Age Aging Antisense Oligonucleotides Atherosclerosis Automobile Driving Blood Vessels CETP gene Cardiometabolic Disease Cardiovascular Diseases Caspase Cells 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 Mediating Metabolic Metabolic syndrome Metabolism Modality Modeling Molecular Mus Obesity Palmitates Pathologic Pathology Pattern Physiology Primary carcinoma of the liver cells Progressive Disease Property Risk Risk Factors Signal Transduction Steatohepatitis Syndrome Testing Therapeutic Transgenic Mice Transgenic Organisms United States Virus age related apolipoprotein E-3 atherosclerosis risk autocrine blood glucose regulation blood lipid cardiometabolism cardiovascular effects cardiovascular risk factor combat coronary fibrosis extracellular fatty liver disease gain of function humanized mouse liver inflammation liver transplantation mouse model mutant non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics overexpression paracrine patient subsets pharmacologic 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项目总结