Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet‐induced mouse model of nonalcoholic fatty liver disease

• Published in: Molecular nutrition & food research Vol. 59; no. 5; pp. 879 - 893
• Main Authors: Pisonero‐Vaquero, Sandra, Martínez‐Ferreras, Ángel, García‐Mediavilla, María Victoria, Martínez‐Flórez, Susana, Fernández, Anna, Benet, Marta, Olcoz, José Luis, Jover, Ramiro, González‐Gallego, Javier, Sánchez‐Campos, Sonia
• Format: Journal Article
• Language: English
• Published: Germany Wiley-VCH 01.05.2015; Blackwell Publishing Ltd
• Subjects: animal models; Animals; CD36 Antigens - physiology; Cells, Cultured; Disease Models, Animal; Fatty acid uptake; fatty acids; fatty liver; gene expression; Gene Expression Regulation - drug effects; genes; inflammation; Lipid metabolism; Lipid Metabolism - drug effects; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; NAFLD; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Oxidative Stress; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - physiology; phosphorylation; PI3K/AKT pathway; Proto-Oncogene Proteins c-akt - physiology; Quercetin; Quercetin - pharmacology; Signal Transduction; transcription (genetics); Fatty acid uptake; NAFLD; Lipid metabolism; Quercetin; PI3K/AKT pathway
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201400913

SCOPE: Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3‐kinase (PI3K)/AKT pathway modulation. METHODS AND RESULTS: We used an in vivo model based on methionine‐ and choline‐deficient (MCD) diet‐fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD‐fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake‐ and trafficking‐related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K‐inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism‐related genes displayed a tendency to normalize in both in vivo and in vitro models. CONCLUSION: These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.