Zili Lei1, Lanxiang Yang2, Yanhong Yang3, Jing Yang2, Zhenpeng Niu2, Xueying Zhang2, Qi Song4, Yuting Lei4, Huijuan Wu2, Jiao Guo5. 1. Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, PR China. Electronic address: 3182683090@qq.com. 2. Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, PR China; School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, PR China. 3. The First Affiliated Hospital (School of Clinical Medicine), Guangdong Pharmaceutical University, Nong-Lin-Xia Road 19#, Yue-Xiu District, Guangzhou, 510080, PR China. 4. Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, PR China. 5. Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, PR China. Electronic address: gyguoyz@163.com.
Abstract
BACKGROUND: Wnt/β-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/β-catenin signaling on regulating hepatocytes metabolism. METHODS: Real-time qPCR, Western blot, and Oil-red O staining methods were used. RESULTS: The Wnt/β-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 IRS-1 (Tyr612) and phosphorylated Akt were decreased. Moreover, the expression of FGF21, FAS, SCD1, PPARγ and ADRP was significantly increased. The expression of ATF4, ATF5, eIF2α, 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/β-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.
BACKGROUND: Wnt/β-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/β-catenin signaling on regulating hepatocytes metabolism. METHODS: Real-time qPCR, Western blot, and Oil-red O staining methods were used. RESULTS: The Wnt/β-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 IRS-1 (Tyr612) and phosphorylated Akt were decreased. Moreover, the expression of FGF21, FAS, SCD1, PPARγ and ADRP was significantly increased. The expression of ATF4, ATF5, eIF2α, 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/β-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.
Authors: Mohammed Alquraishi; Samah Chahed; Dina Alani; Dexter L Puckett; Presley D Dowker; Katelin Hubbard; Yi Zhao; Ji Yeon Kim; Laurentia Nodit; Huma Fatima; Dallas Donohoe; Brynn Voy; Winyoo Chowanadisai; Ahmed Bettaieb Journal: Cell Commun Signal Date: 2022-05-30 Impact factor: 7.525