Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

• Published in: Cell metabolism Vol. 29; no. 2; pp. 383 - 398.e7
• Main Authors: Puchalska, Patrycja, Martin, Shannon E., Huang, Xiaojing, Lengfeld, Justin E., Daniel, Bence, Graham, Mark J., Han, Xianlin, Nagy, Laszlo, Patti, Gary J., Crawford, Peter A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.02.2019
• Subjects: 3-Hydroxybutyric Acid - metabolism; acetoacetate; Acetoacetates - metabolism; Animals; beta-hydroxybutyrate; fibrosis; Hepatocytes - metabolism; Hepatocytes - pathology; immunometabolism; ketone bodies; Liver Cirrhosis, Experimental - metabolism; macrophages; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; nonalcoholic fatty liver disease; stable isotope tracing untargeted metabolomics; macrophages; stable isotope tracing untargeted metabolomics; nonalcoholic fatty liver disease; acetoacetate; immunometabolism; beta-hydroxybutyrate; ketone bodies; fibrosis
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.10.015

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, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]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. [Display omitted] •Macrophages oxidize acetoacetate (AcAc), but not β-hydroxybutyrate•Metabolism of AcAc in macrophages extends into pathways beyond the TCA cycle•Effective AcAc competition with glucose requires its mitochondrial metabolism•Mitochondrial AcAc metabolism in macrophages protects against liver fibrosis Puchalska et al. combine stable isotope tracing with untargeted metabolomics to identify the specific roles of the ketone bodies, acetoacetate (AcAc) and D-β-hydroxybutyrate (D-βOHB), in mediating metabolic plasticity in macrophages. They unveil a hepatocyte-macrophage ketone shuttle and show that AcAc protects the liver from high-fat-diet-induced fibrosis.