Rodrigues Pedro M, Afonso Marta B, Simão André L, Carvalho Catarina C, Trindade Alexandre, Duarte António, Borralho Pedro M, Machado Mariana V, Cortez-Pinto Helena, Rodrigues Cecília Mp, Castro Rui E
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Reproduction and Development, Interdisciplinary Centre of Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal.
Cell Death Dis. 2017 Apr 13;8(4):e2748. doi: 10.1038/cddis.2017.172.
microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target. Strikingly, miR-21 knockout mice fed the FF diet supplemented with farnesoid X receptor (FXR) agonist obeticholic acid (OCA) display minimal steatosis, inflammation, oxidative stress and cholesterol accumulation. In addition, lipoprotein metabolism was restored, including decreased fatty acid uptake and polyunsaturation, and liver and muscle insulin sensitivity fully reinstated. Finally, the miR-21/PPARα axis was found amplified in liver and muscle biopsies, and in serum, of NAFLD patients, co-substantiating its role in the development of the metabolic syndrome. By unveiling that miR-21 abrogation, together with FXR activation by OCA, significantly improves whole body metabolic parameters in NASH, our results highlight the therapeutic potential of nuclear receptor multi-targeting therapies for NAFLD.
最近有研究表明，微小RNA（microRNAs）参与了非酒精性脂肪性肝病（NAFLD）的发病机制，而这种疾病缺乏特异性的药物治疗方法。在这方面，核受体正成为治疗非酒精性脂肪性肝炎（NASH）的关键分子靶点。在此我们发现，在一个典型的NASH相关肝损伤模型中，微小RNA-21（miR-21）缺失导致脂肪变性、炎症和脂肪凋亡逐渐减少，同时纤维化也受到损害。在一个模拟代谢综合征特征的补充快餐（FF）饮食的NASH模型中，肝脏和肌肉中的miR-21水平均升高，同时过氧化物酶体增殖物激活受体α（PPARα）这一关键的miR-21靶点的表达降低。引人注目的是，喂食添加了法尼酯X受体（FXR）激动剂奥贝胆酸（OCA）的FF饮食的miR-21基因敲除小鼠，其脂肪变性、炎症、氧化应激和胆固醇积累均降至最低水平。此外，脂蛋白代谢得以恢复，包括脂肪酸摄取和多不饱和脂肪酸减少，肝脏和肌肉胰岛素敏感性也完全恢复。最后，在NAFLD患者的肝脏和肌肉活检组织以及血清中发现miR-21/PPARα轴被放大，这进一步证实了其在代谢综合征发展中的作用。通过揭示miR-21缺失以及OCA激活FXR可显著改善NASH患者的全身代谢参数，我们的研究结果凸显了核受体多靶点疗法对NAFLD的治疗潜力。
