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

Wonhee Hur, Joon Ho Lee, Sung Woo Kim, Jung Hee Kim, Si Hyun Bae, Minhyung Kim, Daehee Hwang, Young Seok Kim, Taesun Park, Soo Jong Um, Byoung Joon Song, Seung Kew Yoon

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)265-276
Number of pages12
JournalInternational Journal of Biochemistry and Cell Biology
Volume64
DOIs
Publication statusPublished - 2015 May 17

Fingerprint

AMP-Activated Protein Kinases
Palmitates
Fatty Liver
MicroRNAs
Liver
Fatty Acids
Down-Regulation
Cytokines
Hep G2 Cells
High Fat Diet
Genes
Inflammation
Nutrition
Interleukin-8
Innate Immunity
Transcriptional Activation
Liver Diseases
Fats
Tumor Necrosis Factor-alpha
Gene Expression

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology

Cite this

Hur, Wonhee ; Lee, Joon Ho ; Kim, Sung Woo ; Kim, Jung Hee ; Bae, Si Hyun ; Kim, Minhyung ; Hwang, Daehee ; Kim, Young Seok ; Park, Taesun ; Um, Soo Jong ; Song, Byoung Joon ; Yoon, Seung Kew. / Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway. In: International Journal of Biochemistry and Cell Biology. 2015 ; Vol. 64. pp. 265-276.
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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.",
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Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway. / Hur, Wonhee; Lee, Joon Ho; Kim, Sung Woo; Kim, Jung Hee; Bae, Si Hyun; Kim, Minhyung; Hwang, Daehee; Kim, Young Seok; Park, Taesun; Um, Soo Jong; Song, Byoung Joon; Yoon, Seung Kew.

In: International Journal of Biochemistry and Cell Biology, Vol. 64, 17.05.2015, p. 265-276.

Research output: Contribution to journalArticle

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T1 - Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway

AU - Hur, Wonhee

AU - Lee, Joon Ho

AU - Kim, Sung Woo

AU - Kim, Jung Hee

AU - Bae, Si Hyun

AU - Kim, Minhyung

AU - Hwang, Daehee

AU - Kim, Young Seok

AU - Park, Taesun

AU - Um, Soo Jong

AU - Song, Byoung Joon

AU - Yoon, Seung Kew

PY - 2015/5/17

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AB - 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.

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