Regulation of hepatic energy metabolism and gluconeogenesis by BAD

Alfredo Giménez-Cassina, Luisa Garcia-Haro, Cheol Soo Choi, Mayowa A. Osundiji, Elizabeth A. Lane, Hu Huang, Muhammed A. Yildirim, Benjamin Szlyk, Jill K. Fisher, Klaudia Polak, Elaura Patton, Jessica Wiwczar, Marina Godes, Dae Ho Lee, Kirsten Robertson, Sheene Kim, Ameya Kulkarni, Alberto Distefano, Varman Samuel, Gary ClineYoung Bum Kim, Gerald I. Shulman, Nika N. Danial

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)272-284
Number of pages13
JournalCell Metabolism
Volume19
Issue number2
DOIs
StatePublished - Feb 4 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Giménez-Cassina, A., Garcia-Haro, L., Choi, C. S., Osundiji, M. A., Lane, E. A., Huang, H., Yildirim, M. A., Szlyk, B., Fisher, J. K., Polak, K., Patton, E., Wiwczar, J., Godes, M., Lee, D. H., Robertson, K., Kim, S., Kulkarni, A., Distefano, A., Samuel, V., ... Danial, N. N. (2014). Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metabolism, 19(2), 272-284. https://doi.org/10.1016/j.cmet.2013.12.001