Hongwei Yi1, Deyi Xu1, Xudong Wu2, Fang Xu2, Lin Lin1, Huiping Zhou3. 1. 1 Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. 2. 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. 3. 3 Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia.
Abstract
Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress, and lysosome dysfunction. A previous study reported that Isosteviol (ISV), a derivative of stevioside, prevents HFD-induced hepatic injury. However, the underlying mechanisms remain unclear. Results: In this study, we examined the potential cellular/molecular mechanisms underlying ISV-mediated protective effect against FFA-/HFD-induced hepatic lipotoxicity by using both in vitro primary rat hepatocytes and the in vivo rat NAFLD model. The results indicated that ISV inhibits FFA-/HFD-induced hepatic injury via reducing oxidative and ER stress. Specifically, ISV inhibited the expression, activation, and mitochondrial translocation of Src-homology-2-domain-containing transforming protein 1 (p66Shc), an adapter protein that mediates oxidative stress-induced injury and is a substrate of protein kinase C-β (PKC-β), via inhibition of PKC-β activity. However, ISV had no effect on the expression and activity of peptidyl-prolyl cis-trans isomerase and serine/threonine protein phosphatase 2A, isomerase and phosphorylase of p66Shc. In addition, ISV also inhibited FFA-induced ER stress and decreased ER-mitochondrial interaction. Innovation and Conclusion: We first identified that ISV prevents FFA-/HFD-induced hepatic injury through modulating PKC-β/p66Shc/oxidative and ER stress pathways. ISV represents a promising therapeutic agent for NAFLD in the future. Antioxid. Redox Signal. 30, 1949-1968.
Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress, and lysosome dysfunction. A previous study reported that Isosteviol (ISV), a derivative of stevioside, prevents HFD-induced hepatic injury. However, the underlying mechanisms remain unclear. Results: In this study, we examined the potential cellular/molecular mechanisms underlying ISV-mediated protective effect against FFA-/HFD-induced hepatic lipotoxicity by using both in vitro primary rat hepatocytes and the in vivo rat NAFLD model. The results indicated that ISV inhibits FFA-/HFD-induced hepatic injury via reducing oxidative and ER stress. Specifically, ISV inhibited the expression, activation, and mitochondrial translocation of Src-homology-2-domain-containing transforming protein 1 (p66Shc), an adapter protein that mediates oxidative stress-induced injury and is a substrate of protein kinase C-β (PKC-β), via inhibition of PKC-β activity. However, ISV had no effect on the expression and activity of peptidyl-prolyl cis-trans isomerase and serine/threonine protein phosphatase 2A, isomerase and phosphorylase of p66Shc. In addition, ISV also inhibited FFA-induced ER stress and decreased ER-mitochondrial interaction. Innovation and Conclusion: We first identified that ISV prevents FFA-/HFD-induced hepatic injury through modulating PKC-β/p66Shc/oxidative and ER stress pathways. ISV represents a promising therapeutic agent for NAFLD in the future. Antioxid. Redox Signal. 30, 1949-1968.
Entities:
Keywords:
ER stress; Isosteviol; NAFLD; ROS; free fatty acid
Authors: E Migliaccio; M Giorgio; S Mele; G Pelicci; P Reboldi; P P Pandolfi; L Lanfrancone; P G Pelicci Journal: Nature Date: 1999-11-18 Impact factor: 49.962
Authors: Scott V Joy; Ann C Scates; Srilaxmi Bearelly; Moahad Dar; Christina A Taulien; Jason A Goebel; Michael J Cooney Journal: Ann Pharmacother Date: 2005-09-13 Impact factor: 3.154
Authors: Welligton L Braguini; Maria A Biazon Gomes; Brás H de Oliveira; Eva G S Carnieri; Maria Eliane M Rocha; Maria Benigna M de Oliveira Journal: Toxicol Lett Date: 2003-06-05 Impact factor: 4.372
Authors: Zhenyuan Song; Ming Song; David Y W Lee; Yanze Liu; Ion V Deaciuc; Craig J McClain Journal: Basic Clin Pharmacol Toxicol Date: 2007-10 Impact factor: 4.080