Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation

Kevin B. Koronowski, Carolina M. Greco, He Huang, Jin Kwang Kim, Jennifer L. Fribourgh, Priya Crosby, Lavina Mathur, Xuelian Ren, Carrie L. Partch, Cholsoon Jang, Feng Qiao, Yingming Zhao, Paolo Sassone-Corsi

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.

Original languageEnglish (US)
Article number109487
JournalCell Reports
Volume36
Issue number5
DOIs
StatePublished - Aug 3 2021
Externally publishedYes

Keywords

  • AHCY
  • ketogenesis
  • ketogenic diet
  • liver metabolism
  • lysine acylation
  • methionine cycle
  • S-adenosyl-L-homocysteine hydrolase
  • β-hydroxybutyrate
  • β-hydroxybutyrylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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