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

Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway
Hur, W[Hur, Wonhee]Lee, JH[Lee, Joon Ho]Kim, SW[Kim, Sung Woo]Kim, JH[Kim, Jung-Hee]Bae, SH[Bae, Si Hyun]Kim, M[Kim, Minhyung]Hwang, D[Hwang, Daehee]Kim, YS[Kim, Young Seok]Park, T[Park, Taesun]Um, SJ[Um, Soo-Jong]Song, BJ[Song, Byoung-Joon]Yoon, SK[Yoon, Seung Kew]
DGIST Authors
Hwang, D[Hwang, Daehee]
Issue Date
International Journal of Biochemistry and Cell Biology, 64, 265-276
Article Type
Adenylate KinaseAdverse EffectsAnimalAnimal ExperimentAnimal ModelAnimal TissueAnimalsBase SequenceBinding SiteBinding SitesBiosynthesisC57Bl MouseCab39/MO25Calcium-Binding ProteinsCalcium Binding ProteinCell FractionationControlled StudyCytokineCytokine ProductionCytokinesDiet, High-FatDown-RegulationEnzyme Linked Immunosorbent AssayFatty AcidGene ExpressionGeneticsHep G2 Cell LineHep G2 CellsHumanHuman CellHumansImmunoglobulin Enhancer Binding ProteinImmunologyInflammationInnate ImmunityInterleukin-8Lipid DietLiverMaleMetabolismMice, Inbred C57BLMicroRNAMicroRNA-451MicroRNAsMirn451 MicroRNA, MouseMouseMusNon-Alcoholic Fatty LiverNon-Alcoholic Fatty Liver DiseaseNon-Alcoholic SteatohepatitisNon-HumanNucleotide SequencePalmitic AcidProtein Kinase BProto-Oncogene Proteins C-AKTReal Time Polymerase Chain ReactionReverse Transcriptase-Polymerase Chain ReactionSmall Interfering RnaTumor Necrosis Factor-AlphaUnclassified DrugWestern Blotting
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.
Elsevier Ltd
Related Researcher
  • Author Hwang, Dae Hee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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Department of New BiologySystems Biology and Medicine Lab1. Journal Articles

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