Zhang 2024 Cell Metab

Zhang Y, Higgins CB, Tica S, Adams JA, Sun J, Kelly SC, Zong X, Dietzen DJ, Pietka T, Ballentine SJ, Shriver L, Patti G, Cao Y, DeBosch BJ (2024) Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism. Cell Metab [Epub ahead of print]. https://doi.org/10.1016/j.cmet.2024.07.007

» PMID: 39116884 Open Access

Zhang Yiming, Higgins Cassandra B, Tica Stefani, Adams Joshua A, Sun Jiameng, Kelly Shannon C, Zong Xiaoyu, Dietzen Dennis J, Pietka Terri, Ballentine Samuel J, Shriver Leah, Patti Gary, Cao Yin, DeBosch Brian J (2024) Cell Metab

Abstract: 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. • Keywords: Arginase, Diabetes, Fasting, Metabolic dysfunction-associated steatohepatitis, Metabolic dysfunction-associated steatotic liver disease, Nicotinamide adenine dinucleotide, Nicotinamide riboside, Obesity, Tricarboxylic acid cycle, Urea cycle • Bioblast editor: Plangger M • O2k-Network Lab: US MO St Louis Abumrad NA

Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Obesity

Organism: Mouse Tissue;cell: Liver

Coupling state: ET, LEAK, OXPHOS Pathway: N, NS HRR: Oxygraph-2k

2024-08