title: Cyanidin-3-O-β-glucoside protects primary mouse hepatocytes against high glucose-induced apoptosis by modulating mitochondrial dysfunction and the PI3K/Akt pathway.
abstract: Apoptosis is an early event of steatohepatitis in non-alcoholic fatty liver disease (NAFLD), and an increase in oxidative stress induced by hyperglycemia has been linked to an acceleration of apoptosis in hepatocytes. Cyanidin-3-O-β-glucoside (C3G), a classic anthocyanin, has been reported to reduce oxidative stress and attenuate non-alcoholic steatohepatitis in mice. In this study, we evaluated the toxicity of high glucose in primary hepatocytes of mice fed with a high fat diet and amelioration of this toxicity by C3G. Incubation of hepatocytes with 35mM glucose for 12h resulted in a significant decrease in cell viability and increase in apoptotic cell death. Furthermore, hyperglycemia-induced mitochondrial depolarization was accompanied by the release of cytochrome c and altered expression of Bax and Bcl-2, suggesting a mitochondria-mediated apoptotic mode of cell death. Pre-incubation with 50μM C3G induced changes associated with better cell survival and function, including a reduction in reactive species generation, improvement of mitochondrial membrane potential, inactivation of caspase-3 and -9, and down-regulation of the pro-apoptotic Bax protein. We further investigated the role of the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) pathways with respect to the anti-apoptotic action of C3G, and our results showed that C3G could activate Akt. Additionally, C3G inactivated c-Jun N-terminal protein kinase (JNK), but not extracellular signal-regulated kinase or p38 MAPK, in glucose-stressed cells. Interestingly, JNK inhibitor enhanced the protective effect of C3G on cell survival. Our results suggest that anthocyanin C3G may exhibit hepatoprotective potential against NAFLD by promoting functional integrity and survival of hepatocytes.
authors.affiliation: Department of Nutrition, Henry Fok School of Food Science and Engineering, Shaoguan University, Daxue Road, Shaoguan 512005, Guangdong Province, China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health; Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou 510080, China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Guangdong Provincial Key Laboratory of Food, Nutrition and Health; Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou 510080, China.
authors.forename: Xilan
authors.initials: X
authors.lastname: Tang
authors.affiliation: Guangdong Provincial Key Laboratory of Food, Nutrition and Health; Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou 510080, China.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, Henry Fok School of Food Science and Engineering, Shaoguan University, Daxue Road, Shaoguan 512005, Guangdong Province, China.
authors.forename: Guoling
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Nutrition, Henry Fok School of Food Science and Engineering, Shaoguan University, Daxue Road, Shaoguan 512005, Guangdong Province, China. Electronic address: guohh1999@hotmail.com.
authors.forename: Honghui
authors.initials: H
authors.lastname: Guo
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005960:Glucosides / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000872:Anthocyanins; D004041:Dietary Fats; D005960:Glucosides; D047428:Protein Kinase Inhibitors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C462279:cyanidin-3-O-beta-glucopyranoside; D045304:Cytochromes c; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Anthocyanin; Apoptosis; Cyanidin-3-O-β-glucoside; Glucose; Hyperglycemia; LY294002; Mitochondrial dysfunction; Oxidative stress; PD98059; SB203580; SP600125