Glutamine/glutamate metabolism rewiring in reprogrammed human hepatocyte-like cells

Sci Rep. 2019 Nov 29;9(1):17978. doi: 10.1038/s41598-019-54357-x.

Abstract

Human dermal fibroblasts can be reprogrammed into hepatocyte-like (HEP-L) cells by the expression of a set of transcription factors. Yet, the metabolic rewiring suffered by reprogrammed fibroblasts remains largely unknown. Here we report, using stable isotope-resolved metabolic analysis in combination with metabolomic-lipidomic approaches that HEP-L cells mirrors glutamine/glutamate metabolism in primary cultured human hepatocytes that is very different from parental human fibroblasts. HEP-L cells diverge glutamine from multiple metabolic pathways into deamidation and glutamate secretion, just like periportal hepatocytes do. Exceptionally, glutamine contribution to lipogenic acetyl-CoA through reductive carboxylation is increased in HEP-L cells, recapitulating that of primary cultured human hepatocytes. These changes can be explained by transcriptomic rearrangements of genes involved in glutamine/glutamate metabolism. Although metabolic changes in HEP-L cells are in line with reprogramming towards the hepatocyte lineage, our conclusions are limited by the fact that HEP-L cells generated do not display a complete mature phenotype. Nevertheless, our findings are the first to characterize metabolic adaptation in HEP-L cells that could ultimately be targeted to improve fibroblasts direct reprogramming to HEP-L cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cellular Reprogramming
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Glutamic Acid / metabolism*
  • Glutamine / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Lipid Metabolism
  • Metabolome
  • Metabolomics
  • Mice

Substances

  • Glutamine
  • Glutamic Acid