Journal article
A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones
Cell metabolism, Vol.37(1), pp.255-273.e6
01/2025
DOI: 10.1016/j.cmet.2024.10.013
PMCID: PMC11856365
PMID: 39471817
Abstract
Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.
Details
- Title: Subtitle
- A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones
- Creators
- Adam J. Rauckhorst - University of IowaRyan D. Sheldon - University of IowaDaniel J. Pape - University of IowaAdnan Ahmed - University of IowaKelly C. Falls-Hubert - University of IowaRonald A. Merrill - University of IowaReid F. Brown - University of IowaKshitij Deshmukh - University of IowaThomas A. Vallim - University of California, Los AngelesStanislaw Deja - The University of Texas Southwestern Medical CenterShawn C. Burgess - The University of Texas Southwestern Medical CenterEric B. Taylor - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.37(1), pp.255-273.e6
- DOI
- 10.1016/j.cmet.2024.10.013
- PMID
- 39471817
- PMCID
- PMC11856365
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- CELL PRESS
- Grant note
- University of Iowa Fraternal Order of Eagles Diabetes Research CenterNIH: R01DK078184 University of Iowa Healthcare Distinguished Scholar AwardAtkins Foundation: ADA 1-18-PDF-060 AHA: 23PRE1020471, T32 DK112751, P30CA086862
We thank Drs. Bo Ram Kim, Michael Welsh, and Morris Birnbaum for helpful discussions. We are grateful to the University of Iowa Fraternal Order of Eagles Diabetes Research Center Metabolomics Core Facility for technical assistance. This work was supported by NIH R01 DK104998 (E.B.T.) , NIH R01 DK138664 (E.B.T.) , the University of Iowa Healthcare Distinguished Scholar Award (E.B.T.) , NIH K01DK133630 (S.D.) , NIH R01DK078184 (S.C.B.) , the Atkins Foundation (S.C.B.) , ADA 1-18-PDF-060 (A.J.R.) , AHA CDA851976 (A.J.R.) , NIH F32 DK116522 (R.D.S.) , T32 GM007337 to Steven Lentz and AHA 23PRE1020471 (D.J.P.) , NIH T32 DK112751 to Andrew Norris (K.C.F.-H.) , and P30CA086862 to George Weiner, which contributed to sup-port of core facilities utilized for this research.
- Language
- English
- Electronic publication date
- 10/2024
- Date published
- 01/2025
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984738939102771
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