Koop Anja Christina, Thiele Nina Doreen, Steins David, Michaëlsson Erik, Wehmeyer Malte, Scheja Ludger, Steglich Babett, Huber Samuel, Schulze Zur Wiesch Julian, Lohse Ansgar W, Heeren Jörg, Kluwe Johannes
1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany.
Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden.
Hepatol Commun. 2020 Jul 29;4(10):1441-1458. doi: 10.1002/hep4.1566. eCollection 2020 Oct.
Myeloperoxidase (MPO) activity has been associated with the metabolic syndrome, cardiovascular and liver disease. Here, we evaluate the therapeutic potential of MPO inhibition on nonalcoholic steatohepatitis (NASH) and NASH-induced fibrosis, the main determinant of outcomes. MPO plasma levels were elevated in patients with nonalcoholic fatty liver disease (NAFLD) compared with healthy controls. In a second cohort, hepatic messenger RNA expression correlated with higher body mass index and hemoglobin A1c, both being risk factors for NAFLD. We could establish by immunohistochemistry that MPO-positive cells were recruited to the liver in various mouse models of fibrogenic liver injury, including bile duct ligation, carbon tetrachloride (CCl) treatment, spontaneous liver fibrogenesis in multidrug resistance 2 knockout (MDR2 KO) mice, and NASH-inducing diet. Comparison of MPO-deficient mice and their wild-type littermates exposed to a high-caloric diet revealed that MPO deficiency protects against NASH-related liver injury and fibrosis. In line with this, hepatic gene expression analysis demonstrated a MPO-dependent activation of pathways relevant for wound healing, inflammation, and cell death in NASH. MPO deficiency did not affect NAFLD-independent liver injury and fibrosis in MDR2 KO or CCl-treated mice. Finally, we treated wild-type mice exposed to NASH-inducing diet with an oral MPO inhibitor. Pharmacological MPO inhibition not only reduced markers of MPO-mediated liver damage, serum alanine aminotransferase levels, and hepatic steatosis, but also significantly decreased NASH-induced liver fibrosis. MPO inhibitor treatment, but not MPO deficiency, significantly altered gut microbiota including a significant expansion of . MPO specifically promotes NASH-induced liver fibrosis. Pharmacological MPO inhibition attenuates NASH progression and NASH-induced liver fibrosis in mice and is associated with beneficial changes of intestinal microbiota.
髓过氧化物酶（MPO）活性与代谢综合征、心血管疾病和肝脏疾病有关。在此，我们评估抑制MPO对非酒精性脂肪性肝炎（NASH）及NASH诱导的纤维化（结局的主要决定因素）的治疗潜力。与健康对照相比，非酒精性脂肪性肝病（NAFLD）患者的MPO血浆水平升高。在第二个队列中，肝脏信使核糖核酸表达与较高的体重指数和糖化血红蛋白相关，二者均为NAFLD的危险因素。我们通过免疫组织化学证实，在各种纤维化肝损伤小鼠模型中，包括胆管结扎、四氯化碳（CCl）处理、多药耐药2基因敲除（MDR2 KO）小鼠的自发性肝纤维化以及诱导NASH的饮食模型中，MPO阳性细胞被募集至肝脏。对高热量饮食喂养的MPO缺陷小鼠及其野生型同窝小鼠进行比较，结果显示MPO缺陷可预防NASH相关的肝损伤和纤维化。与此一致，肝脏基因表达分析表明，在NASH中，与伤口愈合、炎症和细胞死亡相关的信号通路存在MPO依赖性激活。MPO缺陷并不影响MDR2 KO或CCl处理小鼠中与NAFLD无关的肝损伤和纤维化。最后，我们用口服MPO抑制剂治疗接受诱导NASH饮食的野生型小鼠。药理学上抑制MPO不仅降低了MPO介导的肝损伤标志物、血清丙氨酸氨基转移酶水平和肝脂肪变性，还显著减轻了NASH诱导的肝纤维化。MPO抑制剂治疗而非MPO缺陷显著改变了肠道微生物群，包括 的显著扩增。MPO特异性促进NASH诱导的肝纤维化。药理学上抑制MPO可减轻小鼠NASH的进展和NASH诱导的肝纤维化，并与肠道微生物群的有益变化相关。
