Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Autor:	Zhang Y; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Higgins CB; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Tica S; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Adams JA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Sun J; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Kelly SC; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Zong X; Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., Dietzen DJ; Department of Pediatrics, Washington University School of Medicine, Laboratory Services, St. Louis Children's Hospital, St. Louis, MO 63110, USA., Pietka T; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Ballentine SJ; Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA., Shriver LP; Department of Pediatrics, Washington University School of Medicine, Laboratory Services, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63110, USA., Patti GJ; Department of Pediatrics, Washington University School of Medicine, Laboratory Services, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63110, USA., Cao Y; Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA., DeBosch BJ; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: bdebosch@iu.edu.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Sep 03; Vol. 36 (9), pp. 2069-2085.e8. Date of Electronic Publication: 2024 Aug 07.
DOI:	10.1016/j.cmet.2024.07.007
Abstrakt:	Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2 LKO ) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2 LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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