Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.

Autor:	Selen ES; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Rodriguez S; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Cavagnini KS; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Kim HB; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Na CH; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Wolfgang MJ; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: mwolfga1@jhmi.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Dec; Vol. 298 (12), pp. 102648. Date of Electronic Publication: 2022 Oct 28.
DOI:	10.1016/j.jbc.2022.102648
Abstrakt:	Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (Pcx L-/- ) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. Pcx L-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to Pcx L-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that Pcx L-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in Pcx L-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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