Department of Gastroenterology and Hepatology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.
Clin Exp Pharmacol Physiol. 2018 Aug;45(8):819-831. doi: 10.1111/1440-1681.12940. Epub 2018 Apr 30.
Non-alcoholic fatty liver disease (NAFLD) has been considered as a multi-factorial metabolic syndrome. MicroRNA-375 (MiR-375) was significantly up-regulated in serum of NAFLD patients and the role of miR-375 was addressed as a putative biomarker of NAFLD progression. However, the specific function of miR-375 in the progression of NAFLD is still unclear and the molecular mechanisms underlying NAFLD have yet to be elucidated. Our study aimed at investigating the regulatory role of miR-375 in the molecular mechanisms of the pathogenic progression of NAFLD and to find out whether miR-375 regulates the expression level of adipokines and inflammatory cytokines in NAFLD. We found that miR-375 expression was increased in the serum of high fat diet (HFD)-feeding mice comparing to that in healthy controls, whereas the expression of Adiponectin receptor 2 (AdipoR2) was decreased in mice fed with HFD. Moreover, inhibiton of miR-375 up-regulated the expression of Adiponectin, inhibited the lipid accumulation and down-regulated both the level of Leptin and inflammatory cytokines including tumour necrosis factor (TNF)-α and interleukin (IL)-6 in palmiticacid (PA)-induced human hepatocellular carcinoma HepG2 cells. In addition, we also found that AdipoR2 was a target of miR-375 by binding directly to the 3'UTR of it. Of note, the reduced level of TNF-α, IL-6 as well as Leptin and the production of Adiponectin by miR-375 inhibitors was significantly reversed by silencing of AdipoR2 in PA-induced HepG2 cells. Our findings bring new insight into understanding the complex mechanisms underlying the pathogenesis of NAFLD and provide evidence that miR-375 might represent a novel therapeutic target for NAFLD.
非酒精性脂肪性肝病 (NAFLD) 被认为是一种多因素代谢综合征。在 NAFLD 患者的血清中，miR-375（miR-375）显著上调，miR-375 的作用被认为是 NAFLD 进展的潜在生物标志物。然而，miR-375 在 NAFLD 进展中的具体作用仍不清楚，NAFLD 的分子机制尚未阐明。我们的研究旨在探讨 miR-375 在 NAFLD 发病机制中的调控作用，以及 miR-375 是否调节 NAFLD 中脂肪因子和炎症细胞因子的表达水平。我们发现，与健康对照组相比，高脂肪饮食（HFD）喂养小鼠的血清中 miR-375 表达增加，而 HFD 喂养小鼠的脂联素受体 2（AdipoR2）表达减少。此外，miR-375 的抑制作用上调了脂联素的表达，抑制了脂肪堆积，并下调了棕榈酸（PA）诱导的人肝癌 HepG2 细胞中瘦素和炎症细胞因子（包括肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6））的水平。此外，我们还发现 AdipoR2 是 miR-375 的直接靶点，通过结合其 3'UTR。值得注意的是，miR-375 抑制剂可降低 TNF-α、IL-6、瘦素水平，并增加脂联素的产生，而沉默 AdipoR2 可显著逆转 PA 诱导的 HepG2 细胞中 miR-375 抑制剂的作用。我们的研究结果为理解 NAFLD 发病机制的复杂机制提供了新的见解，并为 miR-375 可能成为 NAFLD 的新治疗靶点提供了证据。
