1. Inhibition of the mTORC1/NF- κ B Axis Alters Amino Acid Metabolism in Human Hepatocytes.
- Author
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Zhang M, Fu Y, Chen Y, Ma Y, Guo Z, Wang Y, Hao H, Fu Q, and Wang Z
- Subjects
- Antibiotics, Antineoplastic pharmacology, Cells, Cultured, Gene Expression Regulation, Hepatocytes cytology, Hepatocytes drug effects, Humans, Ornithine Decarboxylase metabolism, Signal Transduction, Sirolimus pharmacology, Amino Acids metabolism, Hepatocytes metabolism, Mechanistic Target of Rapamycin Complex 1 antagonists & inhibitors, NF-kappa B antagonists & inhibitors
- Abstract
In addition to serving as the building blocks for protein synthesis, amino acids can be used as an energy source, through catabolism. The transamination, oxidative deamination, and decarboxylation processes that occur during amino acid catabolism are catalyzed by specific enzymes, including aspartate aminotransferase (AST), glutamate dehydrogenase (GDH), glutamic acid decarboxylase (GAD), and ornithine decarboxylase (ODC); however, the overall molecular mechanisms through which amino acid catabolism occurs remain largely unknown. To examine the role of mechanistic target of rapamycin complex 1 (mTORC1) on amino acid catabolism, mTORC1 was inactivated by rapamycin or shRNA targeting Raptor , versus activated by overexpressing Rheb or amino acids in human hepatocytes. The expression of amino acid catabolic genes and related transcription factor was investigated by RT/real-time PCR and western blot analysis. A few types of amino acid metabolite were examined by ELISA and HPLC analysis. The data showed that inactivated mTORC1 resulted in inhibition of NF- κ B and the expression of AST , GDH , GAD , and ODC , whereas activated mTORC1 enhanced NF- κ B activation and the expression levels of the catabolism-associated genes. Further, inhibition of NF- κ B reduced the expression levels of AST , GDH , GAD , and ODC . mTORC1 upregulated NF- κ B activation and the expression of AST and ODC in response to glutamate and ornithine treatments, whereas rapamycin inhibited the utilization of glutamate and ornithine in hepatocytes. Taken together, these results indicated that the mTORC1/NF- κ B axis modulates the rate of amino acid catabolism by regulating the expression of key catabolic enzymes in hepatocytes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Meng Zhang et al.)
- Published
- 2021
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