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Cited by 365Biochemical Acid Research StudiesMetabolism, Diabetes, and CancerDiet, Metabolism, and Disease

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

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White, Phillip J., McGarrah, Robert W., Grimsrud, Paul A., Tso, Shih-Chia, Yang, Wen-Hsuan, Haldeman, Jonathan M., Grenier-Larouche, Thomas, An, Jie +13 more·2018·Cell Metabolism
DOI 10.1016/j.cmet.2018.04.015PMC PMC5990471
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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.

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Authors
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., Chuang, D. T., & Newgard, C. B.
Affiliations
  • Duke University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Newgard, Christopher B.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2018-06
Volume
27
Issue
6
Pages
1281-1293.e7
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2018.04.015
PMC
PMC5990471
OpenAlex
W2804969422
Cited by
365
References
55
Citations by year
2026: 50 · 2025: 47 · 2024: 53 · 2023: 58 · 2022: 41 · 2021: 50 · 2020: 24 · 2019: 28 · 2018: 12
FWCI
12.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Pfizer
  • National Institutes of Health (DK083439, DK62306, K08HL135275, PO1-DK58398, DK100425, DK92921)
  • Welch Foundation
  • American Diabetes Association (1-16-INI-17)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords
branched-chain ketoacid dehydrogenase, ATP citrate lyase, branched-chain amino acids, BCAA catabolism, de novo lipogenesis, hepatic steatosis, glucose tolerance, fructose feeding, morbid obesity, lipid metabolism, phosphoproteomics, kinase-phosphatase balance
MeSH terms
Protein Phosphatase 2C, Adolescent, Adult, Aged, Aged, 80 and over, Amino Acids, Branched-Chain, Animals, ATP Citrate (pro-S)-Lyase, Disease Models, Animal, Female, Humans, Male, Middle Aged, Obesity, Rats, Zucker, Rats, Wistar, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide), Lipogenesis, Rats, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, HEK293 Cells

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