Mitochondrial-triggered immune responses mechanistically connect drug-induced steatohepatitis and cardiomyopathy associated with nonalcoholic steatohepatitis.
Mitochondrial-triggered immune responses mechanistically connect drug-induced steatohepatitis and cardiomyopathy associated with nonalcoholic steatohepatitis.
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线粒体触发的免疫反应在机制上将药物引起的脂肪性肝炎和与非酒精性脂肪性肝炎相关的心肌病联系起来。
DOI：
10.1038/s41423-021-00724-6
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发表时间：
2021
影响因子：
24.1
通讯作者：
Njoku,DoloresB
中科院分区：
文献类型：
--
作者：
Wang,Haoran;Pai,Sananda;Ishiyama,Shun;Guo,Xin;Gao,WeiDong;Santhanam,Lakshmi;Gabrielson,Kathy;Njoku,DoloresB
在我们之前的出版物[1]中，我们阐明了调节药物诱导的肝损伤的IL-33依赖性机制。在这篇评论中，我们从机制上将IL-33依赖性药物性脂肪性肝炎与非酒精性脂肪性肝炎联系起来。药物性脂肪性肝炎（DISH）是一种罕见的药物性肝损伤，由能够诱导代谢损伤、脂肪变性或脂肪性肝炎的药物引起[2]。DISH与非酒精性脂肪性肝炎（NASH）不同，因为激发剂是已知的，并且疾病通常在停药后改善。尽管< 2%的NASH病例归因于DISH，但有证据表明DISH可能与NASH具有共同的致病机制。NASH是非酒精性脂肪性肝病（NAFLD）的晚期形式，是一种全身性代谢疾病，其组织学特征为男性、脂肪变性、肝炎、肝细胞气球样变和糖原沉积。NASH和NAFLD男性患者最常见的死亡原因是心肌病、心力衰竭和肥大[3]。然而，NASH或NAFLD与心脏疾病相关的确切机制尚未完全阐明。NAFLD是全球慢性肝病和肝移植的最常见原因[4]。因此，NAFLD/NASH的成功管理具有经济和社会意义。线粒体损伤是药物性肝损伤的主要机制，需要细胞色素P450衍生的反应性代谢产物或母体药物[5]。线粒体损伤和随后的失调通过CYP 2 E1产生的活性氧过量、细胞因子（如IL-6）引发的线粒体脂肪酸氧化水平升高和脂肪酸清除率降低，促进从NAFLD进展为NASH [6]。我们使用线粒体CYP 2 E1的表位开发了一种药物诱导的小鼠脂肪性肝炎模型，该表位通过抑制线粒体复合物I诱导氧化应激[7]。我们对脂肪性肝炎和心肌病的发展进行了15周的随访。我们的研究结果表明，易感宿主（IL-33−/−小鼠）对线粒体表位的免疫应答诱导脂肪性肝炎和心肌病，使人联想到NAFLD、NASH和相关心肌病（图1，补充图2）。1和2），并概括了在人类受试者中观察到的心血管风险增加。具体而言，该表位诱导促炎信号（II 1b、II 17和II 22），触发可能促进II 6和脂肪酸合成并降低脂肪酸清除率的CD 4 + T细胞（CD 4），以及心力衰竭（BNP）和心肌病（Myh 7、lox）（补充图1A）。我们认为该模型为发现NAFLD/NASH、心肌肥厚和心肌病之间的关系以及破译NASH和DISH相关机制提供了机会。使用小鼠模型的研究取决于用于诱导疾病的方法[8]。性别和饮食在疾病发病机制中的复杂作用也可能在研究性激素和NAFLD/NASH时产生结果差异。因此，使用药物诱导的小鼠模型研究NAFLD/NASH的发病机制，其中饮食不是一个因素，并且可以研究性别效应，将产生关于肝脏和心血管系统之间联系的重要机制见解
In our prior publication [1], we elucidated IL-33-dependent mechanisms that regulate drug-induced liver injury. In this commentary, we mechanistically connected IL-33-dependent druginduced steatohepatitis with nonalcoholic steatohepatitis. Druginduced steatohepatitis (DISH) is a rare form of drug-induced liver injury caused by drugs that are capable of inducing metabolic injury, steatosis or steatohepatitis [2]. DISH is distinct from nonalcoholic steatohepatitis (NASH) because the inciting agent is known and the disease generally improves upon drug withdrawal. Although< 2% of NASH cases have been attributed to DISH, evidence suggests that DISH may share pathogenic mechanisms with NASH. NASH is an advanced form of nonalcoholic fatty liver disease (NAFLD) and is a systemic metabolic disease that is histologically characterized by male sex, steatosis, hepatitis, hepatocyte ballooning and glycogen deposition. The most common causes of death in male patients with NASH and NAFLD are cardiomyopathy, heart failure and hypertrophy [3]. However, the exact mechanisms associating NASH or NAFLD with cardiac disease have not been completely elucidated. NAFLD is the most common cause of chronic liver disease and liver transplantation worldwide [4]. Thus, successful management of NAFLD/NASH is both economically and socially significant. Mitochondrial injury, which is a major mechanism of druginduced liver injury, requires cytochrome P450-derived reactive metabolites or the parent drug [5]. Mitochondrial injury and subsequent dysregulation promote the progression from NAFLD to NASH via the overproduction of reactive oxygen species through CYP2E1, increased levels of mitochondrial fatty acid oxidation triggered by cytokines such as IL-6 and reduced fatty acid clearance [6]. We developed a drug-induced model of steatohepatitis in mice using an epitope of mitochondrial CYP2E1 that induces oxidative stress via the inhibition of mitochondrial complex I [7]. We followed steatohepatitis and cardiomyopathy development for 15 weeks. Our results suggest that immune responses to a mitochondrial epitope in a susceptible host (IL-33−/− mice) induce steatohepatitis and cardiomyopathy reminiscent of NAFLD, NASH and associated cardiomyopathy (Fig. 1, Supplementary Figs. 1 and 2) and recapitulate the increased cardiovascular risk noted in human subjects. Specifically, this epitope induces proinflammatory signals (Il1b, Il17, and Il22), triggering CD4+ T cells (CD4) that likely promote Il6 and fatty acid synthesis and reducing fatty acid clearance, as well as heart failure (Bnp) and cardiomyopathy (Myh7, lox)(Supplementary Fig. 1A). We propose that this model provides an opportunity to discover the relationships between NAFLD/NASH, cardiac hypertrophy and cardiomyopathy and decipher the mechanism (s) associated with NASH and DISH. Investigations using mouse models are dependent on the method utilized to induce disease [8]. The complex roles of sex and diet in disease pathogenesis could also produce differences in outcomes when investigating sex hormones and NAFLD/NASH. Thus, investigating the pathogenesis of NAFLD/NASH using a druginduced murine model in which diet is not a factor and sex effects can be investigated will yield important mechanistic insights regarding the link between the liver and the cardiovascular system