Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation
| Autor: | Gregory H. Bird, Accalia Fu, Jarrod A. Marto, A. M. James Shapiro, Loren D. Walensky, Mehmet G. Badur, Scott B. Ficarro, Lindsay Evans, Andrew F. Stewart, Dong Wook Choi, Russell G. Jones, Gaëlle Bridon, Nika N. Danial, Adolfo Garcia-Ocaña, Carolina Rosselot, Daina Avizonis, Hyuk-Soo Seo, Tatsuya Kin, Juan Carlos Alvarez-Perez, Sirano Dhe-Paganon, Esra Karakose, Jurre J. Kamphorst |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Arginine Adolescent Cell Survival Endocrinology Diabetes and Metabolism Citric Acid Cycle Context (language use) Inflammation Carbohydrate metabolism Nitric Oxide Article Nitric oxide chemistry.chemical_compound Young Adult Physiology (medical) Insulin-Secreting Cells Internal Medicine medicine Humans Metabolomics Urea Urea Cycle Disorders Inborn Aged Pyruvate Carboxylase Aspartic Acid Cell Biology Middle Aged Pyruvate carboxylase Cell biology Citric acid cycle Glucose chemistry Urea cycle Female medicine.symptom |
| Zdroj: | Nature metabolism |
| ISSN: | 2522-5812 |
| Popis: | Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomics, biochemical and functional analyses, we investigate the protective versus non-protective effects of glucose in the presence of pro-inflammatory cytokines. When protective, glucose metabolism augments anaplerotic input into the TCA cycle via pyruvate carboxylase (PC) activity, leading to increased aspartate levels. This metabolic mechanism supports the argininosuccinate shunt, which fuels ureagenesis from arginine and conversely diminishes arginine utilization for production of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. Activation of the PC-urea cycle axis is sufficient to suppress NO synthesis and shield cells from death in the context of inflammation and other stress paradigms. Overall, these studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways via PC-directed ureagenesis as a protective mechanism. |
| Databáze: | OpenAIRE |
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