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Cell Metab. 2014 Feb 4;19(2):272-84. doi: 10.1016/j.cmet.2013.12.001.

Regulation of hepatic energy metabolism and gluconeogenesis by BAD.

Author information

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 2Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Division of Endocrinology, Lee Gil Ya Cancer and Diabetes Institute, Gil Medical Center, Gachon University, Incheon 405-760, Korea.
  • 3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
  • 4Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 6Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 7Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nika_danial@dfci.harvard.edu.

Abstract

The homeostatic balance of hepatic glucose utilization, storage, and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed and fasted states. How the liver senses extracellular glucose to cue glucose utilization versus production is not fully understood. We show that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by Bcl-2-associated agonist of cell death (BAD), a protein with roles in apoptosis and metabolism. BAD deficiency reprograms hepatic substrate and energy metabolism toward diminished glycolysis, excess fatty acid oxidation, and exaggerated glucose production that escapes suppression by insulin. Genetic and biochemical evidence suggests that BAD's suppression of gluconeogenesis is actuated by phosphorylation of its BCL-2 homology (BH)-3 domain and subsequent activation of glucokinase. The physiologic relevance of these findings is evident from the ability of a BAD phosphomimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin-resistant and high-fat diet models of diabetes and insulin resistance.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24506868
[PubMed - indexed for MEDLINE]
PMCID:
PMC3971904
Free PMC Article
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