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Prevention and treatment of ALD by inducing hepatic mitochondrial uncoupling

Prevention and treatment of ALD by inducing hepatic mitochondrial uncoupling
诱导肝线粒体解偶联防治ALD
批准号:
9761397
负责人:
Wen-Xing Ding
金额:
$18.73万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-10 至 2021-07-31

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中文摘要
翻译
摘要:酒精性肝病(ALD)是世界性的健康问题。尽管取得了重大进展 由于对ALD的发病机制认识不清,目前尚无有效的治疗方法。 酒精性脂肪变性被认为是ALD的初始触发因素,也是疾病的关键原因 进展,因为它使肝细胞对氧化应激敏感,并导致细胞损伤,从而促进 ALD的发病机制。显然,发现了一种预防/逆转的新的药理学方法 脂肪变性和减轻ALD的肝脏氧化应激,以及了解其潜在的 机制,是迫切需要的。 线粒体是游离脂肪酸等脂质氧化的主要细胞器。线粒体 解偶联是一种促进质子通过线粒体内膜而不产生 三磷酸腺苷。因此,线粒体解偶联可以增加脂质氧化,降低细胞内脂质 积累。线粒体解偶联蛋白(UCPs)可诱导线粒体解偶联。 在小鼠肝脏中异位表达UCP1可增加脂肪酸氧化,减少脂肪堆积,并 保护小鼠免受高脂饮食诱导的肝脏脂肪变性。此外,诱导UCP2的表达是一种 自然细胞对多种类型的细胞氧化应激的反应,如线粒体解偶联 有效减少线粒体活性氧(ROS)的产生。这些发现促使人们 美国推测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,减少肝脏损伤,从而影响ALD的进展。 化学解偶联剂可诱导线粒体解偶联。氯硝柳胺是FDA批准的 驱虫药及其作用机制是诱导寄生虫线粒体解偶联。我们的 最近的研究(NAT.地中海医院。20:1263-1269)证明口服氯硝柳胺乙醇胺盐(NEN) 主要分布在小鼠肝脏和口服NEN中,预防和逆转肝脏脂肪变性和胰岛素抵抗 由高脂肪饮食诱导的小鼠。在一个单独的非酒精性脂肪性肝炎(NASH)小鼠模型中,我们 结果表明,NEN能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。 这项建议的目的是评估线粒体解偶联治疗改善ALD的有效性。 并探讨其潜在的发病机制。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性脑损伤的防治作用 诱导脂肪变性和肝损伤;2.确定线粒体解偶联的机制 防止酒精引起的脂肪变性和肝脏损伤。积极的结果将有助于验证新的 治疗策略,并帮助开发预防和治疗ALD的新治疗选择。
英文摘要
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.
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