Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [ 13 C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[ 13 C]β-hydroxybutyrate (D-βOHB) labeled almost none. [ 13 C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.
Bibliographical noteFunding Information:
The authors thank J. Matthew Gandy and Matthew Longo for mouse husbandry, Peter E. Phelan for guidance on primary macrophage isolation and culture, and Laura Kyro for graphics expertise. This work was supported in part by grants from the NIH ( DK091538 , DK115924 , CA235482 , ES028365 , and OD024624 ). B.D. is supported by the American Heart Association (AHA) postdoctoral fellowship ( 17POST33660450 ).
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- ketone bodies
- nonalcoholic fatty liver disease
- stable isotope tracing untargeted metabolomics