Flux balance analysis predicts Warburg-like effects of mouse hepatocyte deficient in miR-122a

PLoS Comput Biol. 2017 Jul 7;13(7):e1005618. doi: 10.1371/journal.pcbi.1005618. eCollection 2017 Jul.

Abstract

The liver is a vital organ involving in various major metabolic functions in human body. MicroRNA-122 (miR-122) plays an important role in the regulation of liver metabolism, but its intrinsic physiological functions require further clarification. This study integrated the genome-scale metabolic model of hepatocytes and mouse experimental data with germline deletion of Mir122a (Mir122a-/-) to infer Warburg-like effects. Elevated expression of MiR-122a target genes in Mir122a-/-mice, especially those encoding for metabolic enzymes, was applied to analyze the flux distributions of the genome-scale metabolic model in normal and deficient states. By definition of the similarity ratio, we compared the flux fold change of the genome-scale metabolic model computational results and metabolomic profiling data measured through a liquid-chromatography with mass spectrometer, respectively, for hepatocytes of 2-month-old mice in normal and deficient states. The Ddc gene demonstrated the highest similarity ratio of 95% to the biological hypothesis of the Warburg effect, and similarity of 75% to the experimental observation. We also used 2, 6, and 11 months of mir-122 knockout mice liver cell to examined the expression pattern of DDC in the knockout mice livers to show upregulated profiles of DDC from the data. Furthermore, through a bioinformatics (LINCS program) prediction, BTK inhibitors and withaferin A could downregulate DDC expression, suggesting that such drugs could potentially alter the early events of metabolomics of liver cancer cells.

MeSH terms

  • Animals
  • Glucose / metabolism
  • Hepatocytes / metabolism*
  • Humans
  • Liver / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Metabolic Flux Analysis / methods*
  • Metabolomics
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism

Substances

  • MicroRNAs
  • Mirn122 microRNA, mouse
  • Glucose

Grants and funding

This research was supported by grants from the Ministry of Science and Technology of Taiwan (MOST)(https://www.most.gov.tw/) MOST 103-2221-E-194-045-MY3, MOST 104-2627-B 194-001 and MOST 105-2627-M-194-001) to FSW, MOST 104-2320-B-182-017-MY3 to MLC, MOST 104-2627-B-010-001 to CYFH, MOST 104-2627-B-030-001 to JML. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.