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Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation

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Queathem, Eric D., Moazzami, Zahra, Stagg, David B., Nelson, Alisa B., Fulghum, Kyle, Hayir, Abdirahman, Seay, Alisha, Gillingham, Jacob R. +5 more·2025·Science Advances
DOI 10.1126/sciadv.ads0535PMC PMC11777252

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Abstract

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry–based 13 C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl–coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.

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  • Metabolite identities were predicted from exact mass, retention time compared with authentic standards, and tandem mass spectra fragmentation pattern compared with in-house standards and online databases.

    “the identity predicted based on (i) the exact mass calculated from the mass per charge ratio; (ii) retention time compared to authentic standards, and (iii) the tandem mass spectra fragmentation pattern, compared to in-house standards, and online database 57,59,60 .”

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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] .”

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Cited by

Sorted by citations

Authors
Queathem, E. D., Moazzami, Z., Stagg, D. B., Nelson, A. B., Fulghum, K., Hayir, A., Seay, A., Gillingham, J. R., d’Avignon, D. A., Han, X., Ruan, H.-B., Crawford, P. A., & Puchalska, P.
Affiliations
  • University of Minnesota (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
  • Crawford, Peter A.
  • Puchalska, Patrycja
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-01-31
Volume
11
Issue
5
Pages
eads0535-eads0535
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.ads0535
PMC
PMC11777252
OpenAlex
W4406947400
Cited by
30
References
10
Citations by year
2026: 20 · 2025: 9 · 2024: 1
FWCI
9.21
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (AG013319)
  • National Institute on Aging (R01AG069781, P30AG013319)
  • National Heart, Lung, and Blood Institute (T32HL166142, T32HL144472)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK091538, T32DK007203, R25DK140753)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Physiology › Diet and metabolism studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
ketogenesis, ketone bodies, polyunsaturated fatty acids, fatty acid elongation, de novo lipogenesis, acetoacetate, acetoacetyl-CoA synthetase, hepatic lipid metabolism, triglycerides, 13C isotope tracing, hepatocytes

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