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

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.

Mitotically‑associated long non‑coding RNA promotes cancer cell proliferation in hepatocellular carcinoma by downregulating miR‑122a

“…The function of miR-122a has been reported in several human diseases (12)(13)(14)(15). It has been shown that miR-122a is likely involved in Warburg-like effects of hepatocyte deficient in mice (12).…”

“…However, the involvement of MANCR in HCC is unknown. MicroRNA (miR)-122a is a key player in a number of types of diseases including HCC (12)(13)(14)(15)(16). miR-122a is downregulated in HCC and predicted poor survival (16).…”

Systems Biology of Cancer Metastasis

“…Limited to transciptomic processes, ignoring metabolic and proteomic regulation Whole-cell metabolic network modeling (Aguilar et al, 2016;Tsai et al, 2009;Wu et al, 2017): Flux balance and constraint-based reconstruction and analysis (COBRA) (Becker et al, 2007) Able to integrate metabolomic and genomic data…”

Oncogene inference optimization using constraint-based modelling incorporated with protein expression in normal and tumour tissues

“…Wu et al [21] developed a CBM based on the published Recon 2 and the Warburg effects of mouse hepatocytes deficient in miR-122a, and inferred that DDC is an oncogene. A total of 38 metabolic profiles obtained using LC/MS from the liver tissues of 10 control mice and 10 Mir122a −/− mice were applied to CBM for evaluating similarity ratios between the deficient and normal states.…”