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

  • Cell Metab. 2018 Jun 5;27(6):1281-1293.e7. doi: 10.1016/j.cmet.2018.04.015.
Phillip J White  1 ,  Robert W McGarrah  1 ,  Paul A Grimsrud  2 ,  Shih-Chia Tso  3 ,  Wen-Hsuan Yang  2 ,  Jonathan M Haldeman  2 ,  Thomas Grenier-Larouche  2 ,  Jie An  2 ,  Amanda L Lapworth  2 ,  Inna Astapova  1 ,  Sarah A Hannou  2 ,  Tabitha George  2 ,  Michelle Arlotto  2 ,  Lyra B Olson  2 ,  Michelle Lai  4 ,  Guo-Fang Zhang  1 ,  Olga Ilkayeva  2 ,  Mark A Herman  1 ,  R Max Wynn  3 ,  David T Chuang  3 ,  Christopher B Newgard  5
Affiliations
  • 1. Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA; Departments of Medicine and Pharmacology & Cancer Biology, Durham, NC 27701, USA.
  • 2. Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA.
  • 3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • 5. Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA; Departments of Medicine and Pharmacology & Cancer Biology, Durham, NC 27701, USA. Electronic address: [email protected].
PMID: 29779826 DOI: 10.1016/j.cmet.2018.04.015
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.

Keywords
ATP-citrate lyase; branched-chain amino acids; diabetes; lipid metabolism; obesity; systems physiology.