MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis

Int J Mol Med. 2015 Apr;35(4):877-84. doi: 10.3892/ijmm.2015.2092. Epub 2015 Feb 6.

Abstract

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. microRNAs (miRNAs) are small non-coding RNAs that negatively regulate messenger RNA (mRNA). Recently, it was demonstrated that the aberrant expression of certain miRNAs plays a pivotal role in liver disease. The aim of the present study was to evaluate changes in miRNA profiles associated with metformin treatment in a NASH model. Eight-week-old male mice were fed a methionine- and choline-deficient (MCD) diet alone or with 0.08% metformin for 15 weeks. Metformin significantly downregulated the level of plasma transaminases and attenuated hepatic steatosis and liver fibrosis. The expression of miRNA-376a, miRNA‑127, miRNA-34a, miRNA-300 and miRNA-342-3p was enhanced among the 71 upregulated miRNAs, and the expression of miRNA-122, miRNA-194, miRNA-101b and miRNA-705 was decreased among 60 downregulated miRNAs in the liver of MCD-fed mice when compared with control mice. Of note, miRNA profiles were altered following treatment with metformin in MCD-fed mice. miRNA-376a, miRNA‑127, miRNA-34a, miRNA-300 and miRNA-342-3p were downregulated, but miRNA-122, miRNA-194, miRNA‑101b and miRNA-705 were significantly upregulated in MCD-fed mice treated with metformin. miRNA profiles were altered in MCD-fed mice and metformin attenuated this effect on miRNA expression. Therefore, miRNA profiles are a potential tool that may be utilized to clarify the mechanism behind the metformin-induced improvement of hepatic steatosis and liver fibrosis. Furthermore, identification of targetable miRNAs may be used as a novel therapy in human NASH.

MeSH terms

  • Animals
  • Choline Deficiency
  • Cluster Analysis
  • Diet
  • Disease Models, Animal
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / pathology
  • Male
  • Metformin / pharmacology*
  • Methionine / deficiency
  • Mice
  • MicroRNAs / genetics*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Transcriptome*

Substances

  • MicroRNAs
  • Metformin
  • Methionine