Silybin regulates P450s activity by attenuating endoplasmic reticulum stress in mouse nonalcoholic fatty liver disease  

作　　者：Jing Wu Yun-ge Lou Xu-le Yang Rui Wang Ran Zhang Ji-ye Aa Guang-ji Wang Yuan Xie 

机构地区：[1]Key Laboratory of Drug Metabolism and Pharmacokinetics,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing,210009,China

出　　处：《Acta Pharmacologica Sinica》2023年第1期133-144,共12页中国药理学报（英文版）

基　　金：This project was supported by the National Natural Science Foundation of China (No.81872932,81673679);the Six Talent Peaks Project in Jiangsu Province (SWYY-061);the Sanming Project of Medicine in Shenzhen (SZSM201801060);the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University (No.SKLNMZZ202001).

摘　　要：Cytochrome P450s are important phase I metabolic enzymes located on endoplasmic reticulum(ER)involved in the metabolism of endogenous and exogenous substances.Our previous study showed that a hepatoprotective agent silybin restored CYP3A expression in mouse nonalcoholic fatty liver disease(NAFLD).In this study we investigated how silybin regulated P450s activity during NAFLD.C57BL/6 mice were fed a high-fat-diet(HFD)for 8 weeks to induce NAFLD,and were administered silybin(50,100 mg·kg^(−1)·d^(−1),i.g.)in the last 4 weeks.We showed that HFD intake induced hepatic steatosis and ER stress,leading to significant inhibition on the activity of five primary P450s including CYP1A2,CYP2B6,CYP2C19,CYP2D6,and CYP3A in liver microsomes.These changes were dose-dependently reversed by silybin administration.The beneficial effects of silybin were also observed in TG-stimulated HepG2 cells in vitro.To clarify the underlying mechanism,we examined the components involved in the P450 catalytic system,membrane phospholipids and ER membrane fluidity,and found that cytochrome b5(cyt b5)was significantly downregulated during ER stress,and ER membrane fluidity was also reduced evidenced by DPH polarization and lower polyunsaturated phospholipids levels.The increased ratios of NADP+/NADPH and PC/PE implied Ca^(2+) release and disruption of cellular Ca^(2+) homeostasis resulted from mitochondria dysfunction and cytochrome c(cyt c)release.The interaction between cyt c and cyt b5 under ER stress was an important reason for P450s activity inhibition.The effect of silybin throughout the whole course suggested that it regulated P450s activity through its anti-ER stress effect in NAFLD.Our results suggest that ER stress may be crucial for the inhibition of P450s activity in mouse NAFLD and silybin regulates P450s activity by attenuating ER stress.

关 键 词：Non-alcoholic fatty liver disease SILYBIN P450s ER stress cyt b5 cyt c 

分 类 号：R57[医药卫生—消化系统]