Hepatocyte-Macrophage Acetoacetate Shuttle Protects Against Tissue Fibrosis
Open accessAbstract
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.
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Metabolite extraction and LC/MS analysis was performed as described previously.
“Metabolite extraction and LC/MS analysis was performed as described previously [55][56][57] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [56]
A hepatocyte-macrophage acetoacetate exchange blocks fibrogenic signaling to HSCs in a HFD mouse model.
“investigators used a novel metabolomic and stable isotope tracing approach to uncover a hepatocyte-macrophage acetoacetate exchange that blocks fibrogenic signaling to HSCs in a HFD mouse model, although the detailed HSC-macrophage signaling pathways remain uncertain (103).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [103]
Neutrophil and macrophage subsets may blunt HSC activation and promote fibrosis regression.
“Neutrophil and macrophage subsets may blunt HSC activation and promote fibrosis regression as well ( Figure 2 ) (69, 103).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [103]
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The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K. (2019) · Endocrine Reviews · doi:10.1210/er.2019-00034 · Cited by 615 · see citing works
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Ketolysis drives CD8+ T cell effector function through effects on histone acetylation
Luda, K. M., Longo, J., Kitchen-Goosen, S. M., Duimstra, L. R., Ma, E. H., Watson, M. J., Oswald, B. M., Fu, Z., Madaj, Z., Kupai, A., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.07.002 · Cited by 140 · see citing works
Self-citationTargeting cell-intrinsic metabolism for antifibrotic therapy
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Loft, A., Schmidt, S. F., Caratti, G., Stifel, U., Havelund, J., Sekar, R., Kwon, Y., Sulaj, A., Chow, K. K., Alfaro, A. J., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.004 · Cited by 76 · see citing works
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Stubbs, B. J., Koutnik, A. P., Goldberg, E. L., Upadhyay, V., Turnbaugh, P. J., Verdin, E., & Newman, J. C. (2020) · Med · doi:10.1016/j.medj.2020.06.008 · Cited by 71 · see citing works
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Tang, X., Bai, M., Du, X., Wang, H., Liu, M., Fu, X., Zhang, H., Liang, S., & Wang, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1705503 · Cited by 12 · see citing works
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Lysaker, C. R., Johnson, C. N., Csikos, V., Franczak, E., Benson, M., Gilmore, C. A., Birky, C. J., Davis, X., McCoin, C. S., Smith, K. P., et al. (2026) · npj Dementia · doi:10.1038/s44400-026-00105-8 · Cited by 1 · see citing works
Self-citation
- Authors
- Puchalska, P., Martin, S. E., Huang, X., Lengfeld, J. E., Daniel, B., Graham, M. J., Han, X., Nagy, L., Patti, G. J., & Crawford, P. A.
- Affiliations
- University of Minnesota (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Ionis Pharmaceuticals (United States) (US)
- The University of Texas at San Antonio Health Science Center (US)
- Washington University in St. Louis (US)
- Corresponding author
- Crawford, Peter A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 29
- Issue
- 2
- Pages
- 383-398.e7
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6559243
- OpenAlex
- W2901035617
- Cited by
- 138
- References
- 90
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 24 · 2023: 20 · 2022: 20 · 2021: 16 · 2020: 14 · 2019: 7 · 2018: 1
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (DK091538, DK115924, CA235482, ES028365, OD024624)
- American Heart Association (17POST33660450)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- liver fibrosis, ketone bodies, beta-hydroxybutyrate, macrophage polarization, glucose metabolism, mitochondrial metabolism, isotope tracing, untargeted metabolomics
- MeSH terms
- Acetoacetates, Animals, Liver Cirrhosis, Experimental, Macrophages, Mice, Inbred C57BL, Mitochondria, 3-Hydroxybutyric Acid, Hepatocytes, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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