Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9
Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9
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DOI：
10.1172/jci83885
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发表时间：
2016-03-01
影响因子：
15.9
通讯作者：
Mehal, Wajahat Zafar
中科院分区：
文献类型：
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作者：
Garcia-Martinez, Irma;Santoro, Nicola;Mehal, Wajahat Zafar
非酒精性脂肪性肝炎（NASH）是工业化国家最常见的肝病。NASH是一种进行性疾病，可导致肝硬化、癌症和死亡，目前尚无获批的治疗方法。NASH在动物模型中的发展需要完整的TLR9，但在NASH中TLR9通路如何被激活尚不清楚。我们在这项研究中的目标是确定NASH相关的TLR9配体，建立TLR9的细胞需求，并评估肥胖诱导的TLR9通路激活变化的作用。我们证明了来自小鼠和NASH患者的血浆含有高水平的线粒体DNA（mtDNA）和完整的线粒体，并且具有激活TLR9的能力。大多数血浆mtDNA包含在肝细胞来源的微粒（MP）中，从血浆中去除这些MP会导致TLR9活化能力的大幅下降。在小鼠中，响应于高脂肪饮食的NASH发展需要表达溶菌酶的细胞上的TLR9，并且临床上可应用的TLR9拮抗剂在药理学和治疗性给予时阻断NASH的发展。这些数据表明，TLR9通路的激活提供了NASH中关键代谢和炎症表型之间的联系。
Nonalcoholic steatohepatitis (NASH) is the most common liver disease in industrialized countries. NASH is a progressive disease that can lead to cirrhosis, cancer, and death, and there are currently no approved therapies. The development of NASH in animal models requires intact TLR9, but how the TLR9 pathway is activated in NASH is not clear. Our objectives in this study were to identify NASH-associated ligands for TLR9, establish the cellular requirement for TLR9, and evaluate the role of obesity-induced changes in TLR9 pathway activation. We demonstrated that plasma from mice and patients with NASH contains high levels of mitochondrial DNA (mtDNA) and intact mitochondria and has the ability to activate TLR9. Most of the plasma mtDNA was contained in microparticles (MPs) of hepatocyte origin, and removal of these MPs from plasma resulted in a substantial decrease in TLR9 activation capacity. In mice, NASH development in response to a high-fat diet required TLR9 on lysozyme-expressing cells, and a clinically applicable TLR9 antagonist blocked the development of NASH when given prophylactically and therapeutically. These data demonstrate that activation of the TLR9 pathway provides a link between the key metabolic and inflammatory phenotypes in NASH.