Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway.
Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway.
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DOI：
10.1371/journal.pone.0124778
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Dong Y;Gao G;Fan H;Li S;Li X;Liu W
肝脏 X 受体 (LXR) 是葡萄糖代谢的关键转录调节因子，其激活可使血糖正常化并改善胰岛素抵抗啮齿动物模型中的胰岛素敏感性。然而，其分子机制尚不清楚。本研究旨在阐明LXRs介导的体内外肝脏葡萄糖代谢调节机制。使用Db/db小鼠作为糖尿病体内模型；棕榈酸 (PA) 刺激的 HepG2 细胞被用作胰岛素信号传导受损的体外细胞模型。选择 TO901317 (TO) 作为 LXR 激动剂。我们证明，14天的TO治疗有效改善了db/db小鼠的肝脏葡萄糖代谢，包括空腹血糖、空腹胰岛素水平和HOMA-IR。 TO对正常WT小鼠的糖代谢没有影响。 TO 介导的肝脏 LXR 激活导致 ROS 产生强烈抑制，并伴随 JNK 通路失活和 Akt 通路重新激活。 TO 还抑制了 db/db 小鼠中糖异生基因（如 PEPCK 和 G-6-pase）的表达，但在 WT 小鼠中则不然。在 HepG2 细胞中，TO 几乎完全恢复 PA 诱导的 Akt 失活，并抑制 PA 刺激的 ROS 产生和 JNK 激活。有趣的是，HepG2 细胞中 ROS 的基础水平也受到 TO 的抑制。 TO显着抑制PA刺激的糖异生基因的表达。最后，我们发现抗氧化基因，如Nrf2，在TO激活LXR后上调。这些结果有力地支持了这样的观点，即 LXR 的激活对于抑制糖尿病个体的肝脏糖异生和改善胰岛素敏感性至关重要。在分子水平上，作用方式似乎是一样的：在糖尿病状态下，ROS产生增加，JNK被激活，Akt活性被抑制； TO 介导的 LXR 激活可有效抑制 ROS 产生、增加抗氧化基因表达、抑制 JNK 激活并恢复 Akt 活性。我们的数据提供了新的证据支持 LXR 作为抗糖尿病药物开发的有希望的治疗靶点。
Activation of Liver X receptors (LXRs), key transcriptional regulators of glucose metabolism, normalizes glycemia and improves insulin sensitivity in rodent models with insulin resistance. However, the molecular mechanism is unclear. This study is aimed to elucidate the mechanism of LXRs-mediated liver glucose metabolic regulation in vitro and in vivo. Db/db mice were used as an in vivo model of diabetes; palmitate (PA)-stimulated HepG2 cells were used as an in vitro cell model with impairment of insulin signaling. TO901317 (TO) was chosen as the LXRs agonist. We demonstrated that TO treatment for 14 days potently improved the hepatic glucose metabolism in db/db mice, including fasting blood glucose, fasting insulin level, and HOMA-IR. TO had no effect on the glucose metabolism in normal WT mice. TO-mediated activation of hepatic LXRs led to strong inhibition of ROS production accompanied by inactivation of JNK pathway and re-activation of Akt pathway. TO also suppressed the expression of gluconeogenic genes such as PEPCK and G-6-pase in db/db mice, but not in WT mice. In HepG2 cells, TO almost completely restored PA-induced Akt inactivation, and suppressed PA-stimulated ROS production and JNK activation. Interestingly, basal level of ROS was also inhibited by TO in HepG2 cells. TO significantly inhibited PA-stimulated expressions of gluconeogenic genes. Finally, we found that anti-oxidative genes, such as Nrf2, were up-regulated after LXRs activation by TO. These results strongly support the notion that activation of LXRs is critical in suppression of liver gluconeogenesis and improvement of insulin sensitivity in diabetic individuals. At molecular levels, the mode of action appears to be as fellows: under diabetic condition, ROS production is increased, JNK is activated, and Akt activity is inhibited; TO-mediated LXR activation potently inhibits ROS production, increases anti-oxidative gene expressions, suppresses JNK activation, and restores Akt activity. Our data provide new evidence to support LXRs as promising therapeutic targets for anti-diabetic drug development.
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影响因子：
16.2
作者：
Hokayem M;Blond E;Vidal H;Lambert K;Meugnier E;Feillet-Coudray C;Coudray C;Pesenti S;Luyton C;Lambert-Porcheron S;Sauvinet V;Fedou C;Brun JF;Rieusset J;Bisbal C;Sultan A;Mercier J;Goudable J;Dupuy AM;Cristol JP;Laville M;Avignon A
通讯作者：
Avignon A
肝 X 受体激动剂治疗可减轻 2 型糖尿病 db/db 小鼠的心功能障碍
影响因子：
9.3
作者：
He Q;Pu J;Yuan A;Yao T;Ying X;Zhao Y;Xu L;Tong H;He B
通讯作者：
He B
影响因子：
4.8
作者：
Gong, Haibiao;He, Jinhan;Xie, Wen
通讯作者：
Xie, Wen
影响因子：
2.1
作者：
Diaz-Flores, Margarita;Cruz, Miguel;Hernandez-Saavedra, Daniel
通讯作者：
Hernandez-Saavedra, Daniel
影响因子：
4.8
作者：
Cao, GQ;Liang, Y;Etgen, GJ
通讯作者：
Etgen, GJ