Activation of Wnt/β-catenin pathway causes insulin resistance and increases lipogenesis in HepG2 cells via regulation of endoplasmic reticulum stress
Activation of Wnt/β-catenin pathway causes insulin resistance and increases lipogenesis in HepG2 cells via regulation of endoplasmic reticulum stress
复制标题
Wnt/β-连环蛋白途径的激活通过调节内质网应激导致胰岛素抵抗并增加 HepG2 细胞的脂肪生成
DOI：
10.1016/j.bbrc.2020.03.147
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发表时间：
2020-06-04
影响因子：
3.1
通讯作者：
Guo, Jiao
中科院分区：
文献类型：
--
作者：
Lei, Zili;Yang, Lanxiang;Guo, Jiao
背景：Wnt/ β -连环蛋白信号通路参与糖脂代谢，但其机制尚不清楚。目的：研究Wnt/ β -连环蛋白信号通路调节肝细胞代谢的机制。方法：采用Real-time qPCR、Western blot和油红O染色法。结果：CP21R7激活肝细胞Wnt/ β -catenin信号通路，磷酸化的IRS-1 （Ser307）和TRB3水平显著升高，磷酸化的IRS1 （Tyr612）和磷酸化的Alt水平降低。FGF21、FAS、SCD1、PPAR γ和ADRP的表达均显著升高。ATF4、ATF5、eIF2a、GRP78、CHOP表达升高，PERK磷酸化水平升高。TUDCA抑制内质网应激后，FGF21和TRB3的表达显著下调，脂滴明显减少。当STF-083010抑制UPR的IRE1通路时，FGF21的表达显著降低。结论：激活Wnt/ β -catenin信号通路可通过调控内质网应激和UPR的IRE1通路引起肝细胞胰岛素抵抗和脂肪生成，为代谢紊乱的治疗提供新的靶点。(C) 2020爱思唯尔公司版权所有。
Background: Wnt/beta-catenin signaling is involved in glucose and lipid metabolism, but the mechanism is not clear yet.Aim: The objective is to study mechanisms of Wnt/beta-catenin signaling on regulating hepatocytes metabolism.Methods: Real-time qPCR, Western blot, and Oil-red O staining methods were used.Results: The Wnt/beta-catenin signaling was activated in hepatocytes by CP21R7, and the level of phosphorylated IRS-1 (Ser307) and TRB3 were significantly increased, while the levels of phosphorylated IRS1 (Tyr612) and phosphorylated Alt were decreased. Moreover, the expression of FGF21, FAS, SCD1, PPAR gamma and ADRP was significantly increased. The expression of ATF4, ATF5, eIF2a, GRP78, CHOP and phosphorylated level of PERK were also increased. The expression of FGF21 and TRB3 was significantly down-regulated, and the lipid droplets were notably reduced after the ER stress was inhibited by TUDCA. The expression of FGF21 was significantly decreased when the IRE1 pathway of the UPR was inhibited by STF-083010.Conclusions: Activation of Wnt/beta-catenin signaling pathway could cause insulin resistance and lipogenesis in hepatocytes via regulation of the IRE1 pathway of the ER stress and UPR, providing new targets for the treatment of metabolic disorders. (C) 2020 Elsevier Inc. All rights reserved.