Wuxi School of Medicine, Jiangnan University, Wuxi, China.
Food Funct. 2019 Mar 20;10(3):1465-1477. doi: 10.1039/c8fo01452c.
Hepatic microRNAs (miRs) regulate local thyroid hormone (TH) action and TH-related lipid metabolism. We previously found that myricetin effectively ameliorated hepatic steatosis by targeting PPAR signaling pathway, in which the differentially expressed genes were TH-responsive. The present study was designed to explore the mechanism by which myricetin regulated miR-dependent TH action and lipid metabolism on high-fat diet (HFD)-induced hepatic steatosis. C57BL/6J mice were fed a HFD with or without 100 mg kg-1 myricetin by oral gavage for 16 weeks (n = 8 for each group). The results showed that myricetin improved HFD-induced hepatic steatosis, increased serum TH levels and hepatic type 1 deiodinase (DIO1) activities, and elevated energy expenditure in relation to the HFD mice. Meanwhile, myricetin inhibited miR-205 and miR-146b up-regulation induced by HFD, and also up-regulated their targets, Dio1 and thyroid hormone receptor b (TRb) expression, at both the transcriptional and translational levels, accompanied by the regulation of TH responsive lipid metabolism genes. Overexpression or knockdown of miR-205 failed to affect Dio1 mRNA and protein levels in primary mouse hepatocytes. Myricetin directly decreased miR-146b expression in miR-146b mimic-treated hepatocytes to elevate TRb levels. However, the beneficial effects of myricetin on hepatic TH action and lipid metabolism were abolished by TRb siRNA in free fatty acid (FFA)-treated hepatocytes. Our results indicated that myricetin attenuated hepatic steatosis via the miR-146b/TRb pathway and should be considered for the management of NAFLD conditions.
肝 microRNAs（miRs）调节局部甲状腺激素（TH）作用和 TH 相关脂质代谢。我们之前发现杨梅素通过靶向 PPAR 信号通路有效改善肝脂肪变性，其中差异表达的基因是 TH 反应性的。本研究旨在探讨杨梅素调节 miR 依赖的 TH 作用和脂质代谢对高脂肪饮食（HFD）诱导的肝脂肪变性的机制。C57BL/6J 小鼠用 HFD 或 HFD 加 100mgkg-1 杨梅素经口灌胃喂养 16 周（每组 8 只）。结果表明，杨梅素改善了 HFD 诱导的肝脂肪变性，增加了血清 TH 水平和肝 1 型脱碘酶（DIO1）活性，并与 HFD 小鼠的能量消耗增加有关。同时，杨梅素抑制了 HFD 诱导的 miR-205 和 miR-146b 的上调，并在转录和翻译水平上调了它们的靶基因，Dio1 和甲状腺激素受体 b（TRb）的表达，同时调节 TH 反应性脂质代谢基因。在原代小鼠肝细胞中，miR-205 的过表达或敲低均不能影响 Dio1 mRNA 和蛋白水平。杨梅素直接降低 miR-146b 模拟物处理的肝细胞中 miR-146b 的表达，以升高 TRb 水平。然而，在游离脂肪酸（FFA）处理的肝细胞中，用 TRb siRNA 消除了杨梅素对肝 TH 作用和脂质代谢的有益影响。我们的研究结果表明，杨梅素通过 miR-146b/TRb 途径减轻肝脂肪变性，应考虑用于管理非酒精性脂肪性肝病（NAFLD）。
