Simultaneous Induction of Glycolysis and Oxidative Phosphorylation during Activation of Hepatic Stellate Cells Reveals Novel Mitochondrial Targets to Treat Liver Fibrosis

Natalia Smith-Cortinez, Karen van Eunen, Janette Heegsma, Sandra Alejandra Serna-Salas, Svenja Sydor, Lars P Bechmann, Han Moshage, Barbara M Bakker, Klaas Nico Faber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Downloads (Pure)

Abstract

Upon liver injury, hepatic stellate cells (HSCs) transdifferentiate to migratory, proliferative and extracellular matrix-producing myofibroblasts (e.g., activated HSCs; aHSCs) causing liver fibrosis. HSC activation is associated with increased glycolysis and glutaminolysis. Here, we compared the contribution of glycolysis, glutaminolysis and mitochondrial oxidative phosphorylation (OXPHOS) in rat and human HSC activation. Basal levels of glycolysis (extracellular acidification rate similar to 3-fold higher) and particularly mitochondrial respiration (oxygen consumption rate similar to 5-fold higher) were significantly increased in rat aHSCs, when compared to quiescent rat HSC. This was accompanied by extensive mitochondrial fusion in rat and human aHSCs, which occurred without increasing mitochondrial DNA content and electron transport chain (ETC) components. Inhibition of glycolysis (by 2-deoxy-D-glucose) and glutaminolysis (by CB-839) did not inhibit rat aHSC proliferation, but did reduce Acta2 (encoding alpha-SMA) expression slightly. In contrast, inhibiting mitochondrial OXPHOS (by rotenone) significantly suppressed rat aHSC proliferation, as well as Col1a1 and Acta2 expression. Other than that observed for rat aHSCs, human aHSC proliferation and expression of fibrosis markers were significantly suppressed by inhibiting either glycolysis, glutaminolysis or mitochondrial OXPHOS (by metformin). Activation of HSCs is marked by simultaneous induction of glycolysis and mitochondrial metabolism, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC metabolism.

Original languageEnglish
Article number2456
Number of pages15
JournalCells
Volume9
Issue number11
DOIs
Publication statusPublished - Nov-2020

Keywords

  • cell metabolism
  • liver fibrosis
  • mitochondria
  • INHIBITION
  • DYNAMICS

Cite this