Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation

Abstract

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood β-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD⁺/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.

Keywords

sodium butyrate / succinylation / HMGCS2 / ketogenesis / SIRT5

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Acknowledgements

The project was supported by the National Key Research and Development Program of China (No. 2018YFA0800603) and a project (No. 19ZR1439000) of the Shanghai Association for Science and Technology to Jianping Ye.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0943-0 and is accessible for authorized users.

Compliance with ethics guidelines

Yanhong Xu, Xiaotong Ye, Yang Zhou, Xinyu Cao, Shiqiao Peng, Yue Peng, Xiaoying Zhang, Yili Sun, Haowen Jiang, Wenying Huang, Hongkai Lian, Jiajun Yang, Jia Li, and Jianping Ye declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

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