Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver

Cell Metab. 2019 Jun 4;29(6):1291-1305.e8. doi: 10.1016/j.cmet.2019.03.014. Epub 2019 Apr 18.


The hepatic TCA cycle supports oxidative and biosynthetic metabolism. This dual responsibility requires anaplerotic pathways, such as pyruvate carboxylase (PC), to generate TCA cycle intermediates necessary for biosynthesis without disrupting oxidative metabolism. Liver-specific PC knockout (LPCKO) mice were created to test the role of anaplerotic flux in liver metabolism. LPCKO mice have impaired hepatic anaplerosis, diminution of TCA cycle intermediates, suppressed gluconeogenesis, reduced TCA cycle flux, and a compensatory increase in ketogenesis and renal gluconeogenesis. Loss of PC depleted aspartate and compromised urea cycle function, causing elevated urea cycle intermediates and hyperammonemia. Loss of PC prevented diet-induced hyperglycemia and insulin resistance but depleted NADPH and glutathione, which exacerbated oxidative stress and correlated with elevated liver inflammation. Thus, despite catalyzing the synthesis of intermediates also produced by other anaplerotic pathways, PC is specifically necessary for maintaining oxidation, biosynthesis, and pathways distal to the TCA cycle, such as antioxidant defenses.

Keywords: TCA cycle; anaplerosis; gluconeogenesis; high-fat diet; liver physiology; metabolic flux; oxidative stress; pyruvate carboxylase; urea cycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Cell Respiration / genetics
  • Citric Acid Cycle / genetics*
  • Gluconeogenesis / genetics
  • Hepatitis / genetics
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Metabolic Networks and Pathways / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Liver / genetics
  • Mitochondria, Liver / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Pyruvate Carboxylase / genetics*
  • Pyruvate Carboxylase / metabolism


  • Antioxidants
  • Pyruvate Carboxylase