Journal
CELL REPORTS
Volume 25, Issue 8, Pages 2044-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.10.092
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Funding
- ZonMW [91615052]
- Netherlands Heart Foundation [2013T003, 2017T048]
- Spark-Holding BV [2015B002]
- European Union (ITN grant EPIMAC)
- Fondation Leducq [16CVD-01]
- Netherlands CardioVascular Research Initiative
- Dutch Federation of University Medical Centers
- Netherlands Organisation for Health Research and Development
- Royal Netherlands Academy of Sciences [CVON 2011-19, CVON 2017-20]
- Cancer Research UK [C20953/A18644]
- European Union (REPROGRAM [EU Horizon 2020])
- AMC fellowship
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Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function.
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