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

doi:10.1016/j.celrep.2021.109487

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

Cell Rep. 2021 Aug 3;36(5):109487. doi: 10.1016/j.celrep.2021.109487.

Authors

Affiliations

¹ Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: kkoronow@hs.uci.edu.
² Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: grecoc@hs.uci.edu.
³ Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Department of Biological Chemistry, University of California, Irvine School of Medicine, Irvine, CA 92697, USA.
⁵ Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁷ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.

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.

Keywords: AHCY; S-adenosyl-L-homocysteine hydrolase; ketogenesis; ketogenic diet; liver metabolism; lysine acylation; methionine cycle; β-hydroxybutyrate; β-hydroxybutyrylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid / metabolism*
Adenosylhomocysteinase / chemistry
Adenosylhomocysteinase / metabolism
Amino Acid Sequence
Animals
Cell Line
Humans
Ketone Bodies / metabolism*
Liver / metabolism*
Lysine / metabolism*
Male
Mice
Mice, Inbred C57BL
Models, Molecular
NAD / metabolism
Proteomics*

Substances

Ketone Bodies
NAD
Adenosylhomocysteinase
Lysine
3-Hydroxybutyric Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding