Journal
NATURE METABOLISM
Volume 3, Issue 6, Pages 843-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-021-00402-x
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Funding
- National Institutes of Health [2T32AI106704-06, R01-CA214865-01, R01-GM95566-06, R01-AI152044, R01-GM120496, R01-GM135234, R01-GM137203]
- Joseph A. Patrick Research Fellowship in Transplantation
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The research demonstrates that pre-operative exercise protects against liver injury by driving Kupffer cells towards an anti-inflammatory phenotype through itaconate metabolism.
Pre-operative exercise therapy improves outcomes for many patients who undergo surgery. Despite the well-known effects on tolerance to systemic perturbation, the mechanisms by which pre-operative exercise protects the organ that is operated on from inflammatory injury are unclear. Here, we show that four-week aerobic pre-operative exercise significantly attenuates liver injury and inflammation from ischaemia and reperfusion in mice. Remarkably, these beneficial effects last for seven more days after completing pre-operative exercising. We find that exercise specifically drives Kupffer cells toward an anti-inflammatory phenotype with trained immunity via metabolic reprogramming. Mechanistically, exercise-induced HMGB1 release enhances itaconate metabolism in the tricarboxylic acid cycle that impacts Kupffer cells in an NRF2-dependent manner. Therefore, these metabolites and cellular/molecular targets can be investigated as potential exercise-mimicking pharmaceutical candidates to protect against liver injury during surgery. Zhang et al. show that pre-operative exercise protects against liver injury by driving Kupffer cells towards an anti-inflammatory phenotype via itaconate metabolism.
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