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

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

doi:10.1016/j.celrep.2021.109487

Abstract

SUMMARYKetone 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.

Highlights

Ketogenesis provides metabolic intermediates and alternative fuels in many mammalian species (Puchalska and Crawford, 2017; Cahill, 2006)
This process is leveraged during periods of high fatty acid oxidation and diminished carbohydrate availability, as is evident during the neonatal period, fasting, starvation, prolonged exercise, and adherence to a ketogenic diet (KD), where it can become a major contributor to whole-organismal metabolism (Koeslag et al, 1980; McGarry and Foster, 1980; Balasse and Fery, 1989)
We demonstrate that Kbhb directly inhibits the activity of the rate-limiting methionine cycle enzyme Sadenosyl-L-homocysteine hydrolase (AHCY), concurrent with alterations of methionine cycle metabolites

Summary

Introduction

Ketogenesis provides metabolic intermediates and alternative fuels in many mammalian species (Puchalska and Crawford, 2017; Cahill, 2006). Fatty acid oxidation-derived acetyl-CoA produces b-hydroxybutyrate (b-OHB), acetoacetate, and acetone, three primary ketone bodies that are circulated among extrahepatic tissues and metabolized. This process is leveraged during periods of high fatty acid oxidation and diminished carbohydrate availability, as is evident during the neonatal period, fasting, starvation, prolonged exercise, and adherence to a ketogenic diet (KD), where it can become a major contributor to whole-organismal metabolism (Koeslag et al, 1980; McGarry and Foster, 1980; Balasse and Fery, 1989). The predominant fate of b-OHB is terminal oxidation as an energy substrate, evidence demonstrates its involvement in cellular signaling and posttranslational modification (PTM) of histone lysines (Puchalska and Crawford, 2017; Xie et al, 2016; Ruan and Crawford, 2018)

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