The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase

Phillip J. White, Robert W. McGarrah, Paul A. Grimsrud, Shih Chia Tso, Wen Hsuan Yang, Jonathan M. Haldeman, Thomas Grenier-Larouche, Jie An, Amanda L. Lapworth, Inna Astapova, Sarah A. Hannou, Tabitha George, Michelle Arlotto, Lyra B. Olson, Michelle Lai, Guo Fang Zhang, Olga Ilkayeva, Mark A. Herman, R. Max Wynn, David T. ChuangChristopher B. Newgard

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity. Branched-chain amino acids (BCAA) are strongly associated with metabolic diseases. White et al. demonstrate that the kinase (BDK) and phosphatase (PPM1K) that regulate a rate-limiting BCAA metabolic enzyme, BCKDH, also regulate ATP-citrate lyase, a key lipogenic enzyme, thus identifying a new regulatory node that integrates BCAA and lipid metabolism.

Original languageEnglish (US)
Pages (from-to)1281-1293.e7
JournalCell Metabolism
Volume27
Issue number6
DOIs
StatePublished - Jun 5 2018

Keywords

  • ATP-citrate lyase
  • branched-chain amino acids
  • diabetes
  • lipid metabolism
  • obesity
  • systems physiology

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    White, P. J., McGarrah, R. W., Grimsrud, P. A., Tso, S. C., Yang, W. H., Haldeman, J. M., Grenier-Larouche, T., An, J., Lapworth, A. L., Astapova, I., Hannou, S. A., George, T., Arlotto, M., Olson, L. B., Lai, M., Zhang, G. F., Ilkayeva, O., Herman, M. A., Wynn, R. M., ... Newgard, C. B. (2018). The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metabolism, 27(6), 1281-1293.e7. https://doi.org/10.1016/j.cmet.2018.04.015