Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation.
Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation.
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DOI：
10.1038/s42255-020-0199-4
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发表时间：
2020-05
影响因子：
20.8
通讯作者：
Danial NN
中科院分区：
文献类型：
--
作者：
Fu A;Alvarez-Perez JC;Avizonis D;Kin T;Ficarro SB;Choi DW;Karakose E;Badur MG;Evans L;Rosselot C;Bridon G;Bird GH;Seo HS;Dhe-Paganon S;Kamphorst JJ;Stewart AF;James Shapiro AM;Marto JA;Walensky LD;Jones RG;Garcia-Ocana A;Danial NN
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.
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影响因子：
29
作者：
Kolb, Hubert;von Herrath, Matthias
通讯作者：
von Herrath, Matthias
影响因子：
15.9
作者：
Koppe, Laetitia;Nyam, Elsa;Poitout, Vincent
通讯作者：
Poitout, Vincent
影响因子：
56.9
作者：
Grimsby, J;Sarabu, R;Grippo, JF
通讯作者：
Grippo, JF
影响因子：
7.4
作者：
Fuhrer, Tobias;Heer, Dominik;Zamboni, Nicola
通讯作者：
Zamboni, Nicola
影响因子：
7.7
作者：
Cuesta-Muñoz, AL;Huopio, H;Laakso, M
通讯作者：
Laakso, M