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Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway

Title
Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway
Author(s)
Hur, WonheeLee, Joon HoKim, Sung WooKim, Jung-HeeBae, Si HyunKim, MinhyungHwang, DaeheeKim, Young SeokPark, TaesunUm, Soo-JongSong, Byoung-JoonYoon, Seung Kew
Issued Date
2015-07
Citation
International Journal of Biochemistry and Cell Biology, v.64, pp.265 - 276
Type
Article
Author Keywords
Non-alcoholic fatty liverNon-alcoholic steatohepatitisMicroRNAsMicroRNA-451Cab39/MO25Inflammation
Keywords
Adenylate KinaseAdverse EffectsAngiogenesisAnimalAnimal ExperimentAnimal ModelAnimal TissueAnimalsArticleBase SequenceBinding SiteBinding SitesBiosynthesisC57BL MouseCab39/MO25Calcium-Binding ProteinsCalcium Binding ProteinCell FractionationControlled StudyCytokineCytokine ProductionCytokinesDiet, High-FatDOWN-REGULATIONDown RegulationEnzyme Linked Immunosorbent AssayFatty ACIDGene ExpressionGeneticsHep G2 CellsHepg2 Cell LineHumanHuman CellHumansImmunoglobulin Enhancer Binding ProteinImmunologyInflammationINNATE IMMUNITYINTERLEUKIN-8Interleukin 8KINASE ACTIVATIONLipid DietLiverLIVER-DISEASELKB1-STRAD-MO25 COMPLEXMaleMetabolismMice, Inbred C57BLMicrornaMicrorna-451Microrna 451MicrornasMIR-451Mirn451 microRNA, MouseMouseMusNon-Alcoholic Fatty LiverNon-Alcoholic Fatty Liver DiseaseNon-Alcoholic SteatohepatitisNonalcoholic Fatty LiverNonhumanNucleotide SequenceP38 MAPKPalmitic ACIDPATHOGENESISProtein Kinase BProto-Oncogene Proteins C-AKTReal Time Polymerase Chain ReactionREVEALSReverse Transcription Polymerase Chain ReactionSmall Interfering RnaTNF-ALPHATumor Necrosis Factor AlphaUnclassified DrugWestern Blotting
ISSN
1357-2725
Abstract
Mechanisms associated with the progression of non-alcoholic fatty liver disease (NAFLD) remain unclear. We attempted to identify the pattern of altered gene expression at different time points in a high fat diet (HFD)-induced NAFLD mouse model. The early up-regulated genes are mainly involved in the innate immune responses, while the late up-regulated genes represent the inflammation processes. Although recent studies have shown that microRNAs play important roles in hepatic metabolic functions, the pivotal role of microRNAs in the progression of NAFLD is not fully understood. We investigated the functions of miR-451, which was identified as a target gene in the inflammatory process in NAFLD. miR-451 expression was significantly decreased in the palmitate (PA)-exposed HepG2 cells and in liver tissues of HFD-induced non-alcoholic steatohepatitis (NASH) mice. Its decreased expressions were also observed in liver specimens of NASH patients. In vitro analysis of the effect of miR-451 on proinflammatory cytokine provided evidence for negative regulation of PA-induced interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α) production. Furthermore, miR-451 over-expression inhibited translocation of the PA-induced NF-κB p65 subunit into the nucleus. Our result showed that Cab39 is a direct target of miRNA-451 in steatotic cells. Further study showed that AMPK activated through Cab39 inhibits NF-κB transactivation induced in steatotic HepG2 cells. miR-451 over-expression in steatotic cells significantly suppressed PA-induced inflammatory cytokine. These results provide new insights into the negative regulation of miR-451 in fatty acid-induced inflammation via the AMPK/AKT pathway and demonstrate potential therapeutic applications for miR-451 in preventing the progression from simple steatosis to severely advanced liver disease. © 2015 The Authors. Published by Elsevier Ltd.
URI
http://hdl.handle.net/20.500.11750/2885
DOI
10.1016/j.biocel.2015.04.016
Publisher
Elsevier Ltd
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Department of New Biology Systems Biology and Medicine Lab 1. Journal Articles

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