Xinwei Li1, Zhen Shi1, Yiwei Zhu1, Taiyu Shen1, Heyuan Wang2, Guanghou Shui3, Juan J Loor4, Zhiyuan Fang1, Meng Chen1, Xinghui Wang1, Zhicheng Peng1, Yuxiang Song1, Zhe Wang1, Xiliang Du1, Guowen Liu1. 1. Key Laboratory of Zoonoses Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China. 2. The First Hospital of Jilin University, Jilin University, Changchun, China. 3. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. 4. Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Abstract
BACKGROUND AND PURPOSE: Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. EXPERIMENTAL APPROACH: Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. KEY RESULTS: C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. CONCLUSION AND IMPLICATIONS: These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment.
BACKGROUND AND PURPOSE: Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. EXPERIMENTAL APPROACH: Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. KEY RESULTS:C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. CONCLUSION AND IMPLICATIONS: These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment.
Authors: Chrysi Koliaki; Julia Szendroedi; Kirti Kaul; Tomas Jelenik; Peter Nowotny; Frank Jankowiak; Christian Herder; Maren Carstensen; Markus Krausch; Wolfram Trudo Knoefel; Matthias Schlensak; Michael Roden Journal: Cell Metab Date: 2015-05-05 Impact factor: 27.287
Authors: Zhenyu Zhong; Atsushi Umemura; Elsa Sanchez-Lopez; Shuang Liang; Shabnam Shalapour; Jerry Wong; Feng He; Daniela Boassa; Guy Perkins; Syed Raza Ali; Matthew D McGeough; Mark H Ellisman; Ekihiro Seki; Asa B Gustafsson; Hal M Hoffman; Maria T Diaz-Meco; Jorge Moscat; Michael Karin Journal: Cell Date: 2016-02-25 Impact factor: 41.582
Authors: Anton Iershov; Ivan Nemazanyy; Chantal Alkhoury; Muriel Girard; Esther Barth; Nicolas Cagnard; Alexandra Montagner; Dominique Chretien; Elena I Rugarli; Herve Guillou; Mario Pende; Ganna Panasyuk Journal: Nat Commun Date: 2019-04-05 Impact factor: 14.919
Authors: Michael Lazarou; Danielle A Sliter; Lesley A Kane; Shireen A Sarraf; Chunxin Wang; Jonathon L Burman; Dionisia P Sideris; Adam I Fogel; Richard J Youle Journal: Nature Date: 2015-08-12 Impact factor: 49.962
Authors: Siarhei A Dabravolski; Evgeny E Bezsonov; Mirza S Baig; Tatyana V Popkova; Ludmila V Nedosugova; Antonina V Starodubova; Alexander N Orekhov Journal: Int J Mol Sci Date: 2021-04-24 Impact factor: 5.923
Authors: Yan-Qin Li; Fan Zhang; Li-Ping Yu; Jian-Kang Mu; Ya-Qin Yang; Jie Yu; Xing-Xin Yang Journal: Biomed Res Int Date: 2021-10-30 Impact factor: 3.411
Authors: Odetta Antico; Alban Ordureau; Michael Stevens; Francois Singh; Raja S Nirujogi; Marek Gierlinski; Erica Barini; Mollie L Rickwood; Alan Prescott; Rachel Toth; Ian G Ganley; J Wade Harper; Miratul M K Muqit Journal: Sci Adv Date: 2021-11-12 Impact factor: 14.136