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.

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

Greco, Carolina M;
2021

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.
AHCY
S-adenosyl-L-homocysteine hydrolase
ketogenesis
ketogenic diet
liver metabolism
lysine acylation
methionine cycle
β-hydroxybutyrate
β-hydroxybutyrylation
3-Hydroxybutyric Acid
Adenosylhomocysteinase
Amino Acid Sequence
Animals
Cell Line
Humans
Ketone Bodies
Liver
Lysine
Male
Mice, Inbred C57BL
Models, Molecular
NAD
Proteomics
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/70392
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