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

Hua-Qing Wu, Mei-Ling Cheng, Jin-Mei Lai, Hsuan-Hui Wu, Meng-Chun Chen, Wen-Huan Liu, Wu-Hsiung Wu, Peter Mu-Hsin Chang, Chi-Ying F. Huang, Ann-Ping Tsou, Ming-Shi Shiao, Feng-Sheng Wang (+1 others)
2017 PLoS Computational Biology  
The liver is a vital organ involving in various major metabolic functions in human body. 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
more » ... bolic 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. PLOS Computational Biology | https://doi.to JML. The funders had no role Author summary For almost a century, researchers have known that cancer cells have an abnormal metabolism and utilize glucose differently than normal cells do. Aerobic glycolysis or the Warburg effect in cancer cells involves elevated glucose uptake with lactic acid production in the presence of oxygen. MicroRNAs have recently been discovered to be key metabolic regulators that mediate the fine tuning of genes that are involved directly or indirectly in cancer metabolism. 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 modeling (GSMM) of hepatocytes and mouse experimental data with germline deletion of Mir122a (Mir122a -/-) to infer Warburg-like effects. In silico and in vivo observations indicated that DDC overexpression induced Warburg effect in hepatocyte. Furthermore, through a bioinformatics 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. Predicting metabolic reprogramming by flux balance analysis PLOS Computational Biology | https://doi.
doi:10.1371/journal.pcbi.1005618 pmid:28686599 pmcid:PMC5536358 fatcat:6adpisomrjeovkkcihzf5ekuea