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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 Kinase; Adverse Effects; Animal; Animal Experiment; Animal Model; Animal Tissue; Animals; Base Sequence; Binding Site; Binding Sites; Biosynthesis; C57Bl Mouse; Cab39/MO25; Calcium-Binding Proteins; Calcium Binding Protein; Cell Fractionation; Controlled Study; Cytokine; Cytokine Production; Cytokines; Diet, High-Fat; Down-Regulation; Enzyme Linked Immunosorbent Assay; Fatty Acid; Gene Expression; Genetics; Hep G2 Cell Line; Hep G2 Cells; Human; Human Cell; Humans; Immunoglobulin Enhancer Binding Protein; Immunology; Inflammation; Innate Immunity; Interleukin-8; Lipid Diet; Liver; Male; Metabolism; Mice, Inbred C57BL; MicroRNA; MicroRNA-451; MicroRNAs; Mirn451 MicroRNA, Mouse; Mouse; Mus; Non-Alcoholic Fatty Liver; Non-Alcoholic Fatty Liver Disease; Non-Alcoholic Steatohepatitis; Non-Human; Nucleotide Sequence; Palmitic Acid; Protein Kinase B; Proto-Oncogene Proteins C-AKT; Real Time Polymerase Chain Reaction; Reverse Transcriptase-Polymerase Chain Reaction; Small Interfering Rna; Tumor Necrosis Factor-Alpha; Unclassified Drug; Western 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
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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