2. Academic Validation
  3. Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability

  • Cell Metab. 2024 Mar 1:S1550-4131(24)00050-0. doi: 10.1016/j.cmet.2024.02.004.
Stanislaw Deja 1,  Justin A Fletcher 2,  Chai-Wan Kim 3,  Blanka Kucejova 3,  Xiaorong Fu 4,  Monika Mizerska 3,  Morgan Villegas 3,  Natalia Pudelko-Malik 5,  Nicholas Browder 3,  Melissa Inigo-Vollmer 3,  Cameron J Menezes 6,  Prashant Mishra 6,  Eric D Berglund 7,  Jeffrey D Browning 8,  John P Thyfault 9,  Jamey D Young 10,  Jay D Horton 11,  Shawn C Burgess 12
Affiliations

Affiliations

  • 1 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 2 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 3 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 4 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 5 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland.
  • 6 Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 7 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 8 Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 9 Departments of Cell Biology and Physiology, Internal Medicine and KU Diabetes Institute, Kansas Medical Center, Kansas City, KS, USA.
  • 10 Department of Chemical and Biomolecular Engineering, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA.
  • 11 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. Electronic address: jay.horton@utsouthwestern.edu.
  • 12 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. Electronic address: shawn.burgess@utsouthwestern.edu.
PMID: 38447582 DOI: 10.1016/j.cmet.2024.02.004
Abstract

Acetyl-CoA Carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting Amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

Keywords

Nrf2; TCA cycle; acetyl-CoA carboxylase; anaplerosis; autophagy; gluconeogenesis; lipogenesis; malonyl-CoA; protein synthesis; proteolysis.

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