Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.
School of Life Science, Shanxi Normal University, Linfen City, China.
Hepatology. 2019 Apr;69(4):1488-1503. doi: 10.1002/hep.30301. Epub 2019 Jan 7.
Nonalcoholic fatty liver disease (NAFLD) is a major risk factor of many end-stage liver diseases. Alterations in microRNA expression have been reported in patients with NAFLD. However, the transcriptional mechanism(s) of dysregulated microRNAs under the state of NAFLD is poorly described, and microRNAs that regulate the pathogenesis of NAFLD synergistically with their regulators remain unknown. Here we report that microRNA-378 expression is significantly increased in fatty livers of mice and patients with NAFLD. Although microRNA-378 locates within the intron of Ppargc1β (peroxisome proliferator-activated receptor γ coactivator 1-beta), there was a significant uncoupling of Ppargc1β mRNA and microRNA-378 levels in both sources of fatty livers. Further studies identified a full-length primary transcript of microRNA-378. LXRα (liver X receptor alpha) functioned as a transcription activator of microRNA-378 and a repressor of Ppargc1β transcription. It is known that miR-378 is an inhibitor of fatty acid oxidation (FAO) and the function of Ppargc1β is opposite to that of miR-378. GW3965 treatment (LXRα agonist) of murine hepatocytes and mice increased microRNA-378 and reduced Ppargc1β, which subsequently impaired FAO and aggravated hepatosteatosis. In contrast, additional treatment of miR-378 inhibitor or Ppargc1β, which knocked down increased miR-378 or recovered expression of Ppargc1β, offset the effects of GW3965. Liver-specific ablation of Lxrα led to decreased miR-378 and increased Ppargc1β, which subsequently improved FAO and reduced hepatosteatosis. Conclusion: Our findings indicated that miR-378 possesses its own transcription machinery, which challenges the well-established dogma that miR-378 transcription is controlled by the promoter of Ppargc1β. LXRα selectively activates transcription of miR-378 and inhibits expression of Ppargc1β, which synergistically impairs FAO. In addition to lipogenesis, impaired FAO by miR-378 in part contributes to LXRα-induced hepatosteatosis.
非酒精性脂肪性肝病 (NAFLD) 是许多终末期肝病的主要危险因素。已有报道称，NAFLD 患者的 miRNA 表达发生改变。然而，NAFLD 状态下失调 miRNA 的转录机制描述甚少，并且与调节剂协同调节 NAFLD 发病机制的 miRNA 仍不清楚。本研究报告称，miR-378 在小鼠和 NAFLD 患者的脂肪肝中表达显著增加。尽管 miR-378 位于 Ppargc1β（过氧化物酶体增殖物激活受体 γ 共激活因子 1-β）的内含子中，但在这两种来源的脂肪肝中，Ppargc1β mRNA 和 miR-378 水平之间存在显著的解偶联。进一步的研究确定了 miR-378 的全长初级转录本。LXRα（肝 X 受体 α）作为 miR-378 的转录激活子和 Ppargc1β 转录的抑制剂发挥作用。已知 miR-378 是脂肪酸氧化 (FAO) 的抑制剂，而 Ppargc1β 的功能与 miR-378 相反。GW3965（LXRα 激动剂）处理小鼠肝细胞和小鼠增加了 miR-378 并减少了 Ppargc1β，随后损害了 FAO 并加重了肝脂肪变性。相比之下，额外的 miR-378 抑制剂或 Ppargc1β 的处理，敲低增加的 miR-378 或恢复 Ppargc1β 的表达，抵消了 GW3965 的作用。肝特异性敲除 Lxrα 导致 miR-378 减少和 Ppargc1β 增加，随后改善了 FAO 并减少了肝脂肪变性。结论：我们的研究结果表明，miR-378 具有自己的转录机制，这挑战了 miR-378 转录受 Ppargc1β 启动子控制的既定教条。LXRα 选择性地激活 miR-378 的转录并抑制 Ppargc1β 的表达，协同损害 FAO。除了脂肪生成外，miR-378 引起的 FAO 受损部分导致 LXRα 诱导的肝脂肪变性。
