Prevention and treatment of ALD by inducing hepatic mitochondrial uncoupling

摘要：酒精性肝病（ALD）是一个全球性的健康问题。尽管取得了重大进展 在对发病机制和机制的理解上，ALD没有有效的治疗方法。 酒精性脂肪变性被认为是ALD的初始触发因素，也是疾病的关键致病因素 进展，因为它使肝细胞对氧化应激敏感，并引起细胞损伤，促进肝细胞的增殖。 ALD的发病机制显然，鉴定一种新的药理学方法用于预防/逆转 脂肪变性和减少ALD中的肝脏氧化应激，以及了解 这些机制是迫切需要的。 线粒体是脂质如游离脂肪酸被氧化的主要细胞器。线粒体 解偶联是一个过程，促进质子流入线粒体内膜，而不产生 ATP因此，线粒体解偶联可增加脂质氧化，降低细胞内脂质 积累线粒体解偶联可以由线粒体解偶联蛋白（UCPs）诱导。 在小鼠肝脏中异位表达UCP1增加脂肪酸氧化，减少脂质积累， 保护小鼠免受高脂饮食诱导的肝脂肪变性。此外，UCP2表达的诱导是一个重要因素。 对许多类型的细胞氧化应激的自然细胞反应，如线粒体解偶联 有效减少线粒体活性氧（ROS）的产生。这些发现促使 我们假设诱导肝脏线粒体解偶联是一种有效的治疗策略， 治疗酒精性脂肪变性和减少肝损伤，从而影响ALD进展。 线粒体解偶联可由化学解偶联剂诱导。氯硝柳胺是FDA批准的 抗蠕虫药物及其作用机制是诱导寄生虫的线粒体解偶联。我们 最近的研究（Nat.Med.20：1263 - 1269）表明，口服氯硝柳胺乙醇胺盐（NEN） 主要分布在小鼠肝脏，口服NEN可预防和逆转肝脏脂肪变性和胰岛素抵抗 高脂饮食诱导的小鼠。在一个单独的非酒精性脂肪性肝炎（NASH）小鼠模型中， 表明NEN可以显著改善肝脏炎症和纤维化症状。 我们的长期目标是发现新的治疗策略，并开发有效的ALD治疗方法。 本提案的目的是评估线粒体解偶联对改善ALD的有效性。 症状并研究其潜在机制。提出了两个具体目标：1。审查 NEN和UCP1诱导的线粒体解偶联对酒精的预防和治疗作用， 诱导脂肪变性和肝损伤; 2.来确定线粒体解偶联的机制 防止酒精引起的脂肪变性和肝损伤。积极的成果将有助于验证新的 治疗策略，并帮助开发新的治疗方案，预防和治疗ALD。

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.