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Prevention and treatment of ALD by inducing hepatic mitochondrial uncoupling

诱导肝线粒体解偶联防治ALD

基本信息

批准号：
9761397
负责人：
Wen-Xing Ding
金额：
$ 18.73万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761397
关键词：
5&apos -AMP-activated protein kinase ATP Synthesis Pathway Acetyl-CoA Carboxylase Acute Alcoholic Liver Diseases Alcohols Anthelmintics Bioenergetics Chemicals Chronic Cirrhosis Cytoplasm Disease Progression Effectiveness Electron Transport Ethanol Ethanolamines FDA approved Fatty Acids Fatty Liver Fibrosis Futile Cycling Goals Health Helminths Hepatic Hepatocyte Hepatotoxicity High Fat Diet Inflammation Inner mitochondrial membrane Insulin Resistance Intervention Intracellular Accumulation of Lipids Lipids Liver Liver Mitochondria Metabolic Mitochondria Modeling Mus NADH Nonesterified Fatty Acids Oral Organelles Outcome Oxidation-Reduction Oxidative Stress Oxides Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Prevention Preventive Primary carcinoma of the liver cells Process Production Proton Pump Protons Reactive Oxygen Species Regulation Research Research Personnel Signal Pathway Sodium Chloride Symptoms Testing Therapeutic Therapeutic Effect Therapeutic Studies Transgenes Transgenic Mice Treatment Efficacy Weight Gain base effective therapy fatty acid oxidation genetic approach genetic manipulation improved liquid chromatography mass spectrometry liver injury metabolomics mitochondrial uncoupling protein mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics oxidation oxidative damage prevent problem drinker prototype response

项目摘要

Summary: Alcoholic liver disease (ALD) is a health problem worldwide. Despite significant progresses made on the understanding of the pathogenesis and mechanisms, no effective treatment for ALD is available. Alcoholic steatosis is considered as the initial trigger of ALD and a critical causal factor for disease progression, as it sensitizes hepatocytes to oxidative stress and causes cellular damages that promote the pathogenesis of ALD. Clearly, identification of a novel pharmacological approach for preventing /reversing steatosis and for reducing hepatic oxidative stress in ALD, as well as understanding the underlying mechanisms, are urgently needed. Mitochondrion is the main organelle where lipids such as free fatty acid are oxidized. Mitochondrial uncoupling is a process that facilitates proton influx across mitochondrial inner membrane without generating ATP. As a result, mitochondrial uncoupling can increase lipid oxidation and reduce intracellular lipid accumulation. Mitochondrial uncoupling can be induced by mitochondrial uncoupler proteins (UCPs). Ectopically expressing UCP1 in mouse liver increases fatty acid oxidation, reduces lipid accumulation, and protects mice from high-fat diet-induced hepatic steatosis. Moreover, induction of UCP2 expression is a natural cellular response towards many types of cellular oxidative stress, as mitochondrial uncoupling effectively reduces the production of mitochondrial reactive oxygen species (ROS). These findings prompted us to hypothesize that induction of mitochondrial uncoupling in liver is an effective therapeutic strategy for treating alcoholic steatosis and reducing hepatic damage, thereby impacting on ALD progression. Mitochondrial uncoupling can be induced by chemical uncouplers. Niclosamide is an FDA approved anthelmintic drug and its mechanism of action is to induce mitochondrial uncoupling of parasitic worms. Our recent study (Nat. Med. 20: 1263-1269) demonstrated that oral niclosamide ethanolamine salt (NEN) is mainly distributed in mouse liver and oral NEN prevents and reverses hepatic steatosis and insulin resistance induced by a high-fat diet in mice. In a separate non-alcoholic steatohepatitis (NASH) mouse model, we showed that NEN can dramatically improve hepatic inflammation and fibrosis symptoms. Our long-term goal is to discover novel therapeutic strategies and develop effective therapeutics for ALD. The objective of this proposal is to evaluate the effectiveness of mitochondrial uncoupling on improving ALD symptoms and to investigate the underlying mechanisms. Two Specific Aims are proposed: 1. to examine the preventive and therapeutic effects of NEN- and UCP1- induced mitochondrial uncoupling on alcohol- induced steatosis and liver injury; 2. to determine the mechanisms by which mitochondrial uncoupling protects against alcohol-induced steatosis and liver injury. Positive outcomes will help validate a new therapeutic strategy and help develop new therapeutic options for the prevention and treatment of ALD.

摘要：酒精性肝病（ALD）是一个世界性的健康问题。尽管取得了重大进展