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Journal article
ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch
Cell reports (Cambridge), v 17(4), pp 1037-1052
18 Oct 2016
PMID: 27760311
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-coenzyme A (CoA) plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here, we show that, upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY), cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL) and histone acetylation. A physiological level of acetate is sufficient for cell viability and abundant acetyl-CoA production, although histone acetylation levels remain low in ACLY-deficient cells unless supplemented with high levels of acetate. ACLY-deficient adipocytes accumulate lipid in vivo, exhibit increased acetyl-CoA and malonyl-CoA production from acetate, and display some differences in fatty acid content and synthesis. Together, these data indicate that engagement of acetate metabolism is a crucial, although partial, mechanism of compensation for ACLY deficiency.
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•ACSS2 is upregulated upon genetic deletion of Acly in vitro and in vivo•Acetate sustains viability in Acly-deficient MEFs, but proliferation is impaired•Low levels of acetate can supply abundant acetyl-CoA in the absence of ACLY•Acetate partially rescues lipogenesis and histone acetylation in ACLY deficiency
Zhao et al. demonstrate that ACLY deficiency causes upregulation of ACSS2 in proliferating cells in vitro and adipocytes in vivo. Acetate is needed for viability and is used for lipid synthesis and histone acetylation in the absence of ACLY. Proliferation is constrained in ACLY-deficient cells, despite ACSS2 compensation.
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Details
- Title
- ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch
- Creators
- Steven Zhao - Cancer Research InstituteAnnMarie Torres - University of PennsylvaniaRyan A. Henry - Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USASophie Trefely - Drexel UniversityMartina Wallace - University of California, San DiegoJoyce V. Lee - Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAlessandro Carrer - University of PennsylvaniaArjun Sengupta - Translational TherapeuticsSydney L. Campbell - Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAYin-Ming Kuo - Fox Chase Cancer CenterAlexander J. Frey - A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USANoah Meurs - University of California, San DiegoJohn M. Viola - Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAIan A. Blair - Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAalim M. Weljie - Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAChristian M. Metallo - Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USANathaniel W. Snyder - A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USAAndrew J. Andrews - Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USAKathryn E. Wellen - Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Publication Details
- Cell reports (Cambridge), v 17(4), pp 1037-1052
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000385853600011
- Scopus ID
- 2-s2.0-84994840428
- Other Identifier
- 991019167782004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology