title: ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch.
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.
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: AnnMarie
authors.initials: A
authors.lastname: Torres
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Henry
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Trefely
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Wallace
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Joyce V
authors.initials: JV
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carrer
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Campbell
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Kuo
authors.affiliation: A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Frey
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Meurs
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Viola
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Aalim M
authors.initials: AM
authors.lastname: Weljie
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.affiliation: A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andrews
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wellenk@exchange.upenn.edu.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000172:deficiency / Q000378:metabolism*; D000106:Acetate-CoA Ligase / Q000378:metabolism; D000085:Acetates / Q000378:metabolism* / Q000494:pharmacology; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000085:Acetates; D006657:Histones; D008055:Lipids; D000105:Acetyl Coenzyme A; D001275:ATP Citrate (pro-S)-Lyase; C000595378:ACSS2 protein, mouse; D000106:Acetate-CoA Ligase; D005947:Glucose
keywords: ACLY; ACSS2; acetate; acetyl-CoA; acetylation; adipose tissue; fatty acid synthesis; metabolic flexibility; metabolism