Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut, USA.
Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.
JCI Insight. 2017 Nov 2;2(21):96094. doi: 10.1172/jci.insight.96094.
Accumulation of lipid droplets and inflammatory cell infiltration is the hallmark of nonalcoholic steatohepatitis (NASH). The roles of noncoding RNAs in NASH are less known. We aim to elucidate the function of miR-141/200c in diet-induced NASH. WT and miR-141/200c-/- mice were fed a methionine and choline deficient (MCD) diet for 2 weeks to assess markers of steatosis, liver injury, and inflammation. Hepatic miR-141 and miR-200c RNA levels were highly induced in human patients with NASH fatty liver and in WT MCD mice. miR-141/200c-/- MCD mice had reduced liver weights and triglyceride (TG) levels, which was associated with increased microsomal TG transfer protein (MTTP) and PPARα but reduced SREBP1c and FAS expression. Inflammation was attenuated and F4/80 macrophage activation was suppressed in miR-141/200c-/- mice, as evidenced by decreased serum aminotransferases and IL-6 and reduced hepatic proinflammatory, neutrophil, and profibrotic genes. Treatment with LPS in BM-derived macrophages isolated from miR-200c/141-/- mice polarized macrophages toward the M2 antiinflammatory state by increasing Arg1 and IL-10 levels while decreasing the M1 marker iNOS. In addition, elevated phosphorylated AMPK (p-AMPK), p-AKT, and p-GSK3β and diminished TLR4 and p-mTOR/p-4EBP1 proteins were observed. Lipidomics and metabolomics revealed alterations of TG and phosphatidylcholine (PC) lipid species by miR-141/200c deficiency. In summary, miR-141/200c deficiency diminished NASH-associated hepatic steatosis and inflammation by reprogramming lipid and inflammation signaling pathways.
脂滴积累和炎症细胞浸润是非酒精性脂肪性肝炎（NASH）的标志。非编码 RNA 在 NASH 中的作用知之甚少。我们旨在阐明 miR-141/200c 在饮食诱导的 NASH 中的作用。WT 和 miR-141/200c-/- 小鼠喂食蛋氨酸和胆碱缺乏（MCD）饮食 2 周，以评估脂肪变性、肝损伤和炎症的标志物。NASH 脂肪肝患者和 WT MCD 小鼠的肝 miR-141 和 miR-200c RNA 水平高度诱导。miR-141/200c-/- MCD 小鼠的肝重和甘油三酯（TG）水平降低，这与微粒体 TG 转移蛋白（MTTP）和 PPARα 增加但 SREBP1c 和 FAS 表达减少有关。miR-141/200c-/- 小鼠的炎症减轻，F4/80 巨噬细胞活化受到抑制，这表现在血清转氨酶和 IL-6 降低，肝前炎症、中性粒细胞和促纤维化基因减少。用 LPS 处理从 miR-200c/141-/- 小鼠分离的 BM 来源的巨噬细胞，通过增加 Arg1 和 IL-10 水平同时降低 M1 标志物 iNOS，将巨噬细胞极化到 M2 抗炎状态。此外，还观察到升高的磷酸化 AMPK（p-AMPK）、p-AKT 和 p-GSK3β 以及降低的 TLR4 和 p-mTOR/p-4EBP1 蛋白。脂质组学和代谢组学显示 miR-141/200c 缺乏导致 TG 和磷脂酰胆碱（PC）脂质种类发生变化。总之，miR-141/200c 缺乏通过重新编程脂质和炎症信号通路，减少与 NASH 相关的肝脂肪变性和炎症。
