Activation of Wnt/beta-catenin pathway causes insulin resistance and increases lipogenesis in HepG2 cells via regulation of endoplasmic reticulum stress
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Lei, Zili; Yang, Lanxiang; Yang, Yanhong; Yang, Jing; Niu, Zhenpeng; Zhang, Xueying; Song, Qi; Lei, Yuting; Wu, Huijuan; Guo, Jiao
Abstract
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.
Antidiabetic Potential of Green Seaweed Enteromorpha prolifera Flavonoids Regulating Insulin Signaling Pathway and Gut Microbiota in Type 2 Diabetic Mice
JOURNAL OF FOOD SCIENCE
Authors: Yan, Xin; Yang, Chengfeng; Lin, Guopeng; Chen, Yuqing; Miao, Song; Liu, Bin; Zhao, Chao
Abstract
This study aimed to investigate the antidiabetic activity of water-ethanol extract of green macroalgae Enteromorpha prolifera (EPW) and its flavonoid-rich fraction less than 3 kDa (EPW3) in type 2 diabetic mice induced by streptozotocin and a high-sucrose/high-fat diet. The major active compounds were identified using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight-tandem mass spectrometry. Quantitative gene expression analysis of the insulin signaling pathway was performed. The effects of EPW3 on gut microflora in diabetic mice were analyzed by high-throughput 16S rRNA gene sequencing. The results showed EPW3 treatment decreased the fasting blood glucose, improved oral glucose tolerance, and protected against liver and kidney injury with reduced inflammation in diabetic mice. The active principle of EPW3 revealed hypoglycemic effect as indicated by activation of the IRS1/PI3K/AKT and inhibition of the JNK1/2 insulin pathway in liver. Furthermore, the treatment significantly enriched the abundance of Lachnospiraceae and Alisties, which were positive correlation of metabolic phenotypes. These findings indicated that EPW3 possessed great therapeutic potential as adjuvant therapy for type 2 diabetes.