Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

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, [C-13] acetoacetate (AcAc) labeled similar to 200 chemical features, but its reduced form D-[C-13]beta-hydroxybutyrate (D-beta OHB) labeled almost none. [C-13]glucose labeled similar to 500 features, and while unlabeled AcAc competed with only similar to 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-beta OHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-beta OHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.