ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch

Cell Rep. 2016 Oct 18;17(4):1037-1052. doi: 10.1016/j.celrep.2016.09.069.


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.

Keywords: ACLY; ACSS2; acetate; acetyl-CoA; acetylation; adipose tissue; fatty acid synthesis; metabolic flexibility; metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Citrate (pro-S)-Lyase / deficiency
  • ATP Citrate (pro-S)-Lyase / metabolism*
  • Acetate-CoA Ligase / metabolism
  • Acetates / metabolism*
  • Acetates / pharmacology
  • Acetyl Coenzyme A / metabolism
  • Acetylation
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Deletion
  • Glucose / metabolism*
  • Histones / metabolism
  • Lipid Metabolism / drug effects
  • Lipids / biosynthesis
  • Male
  • Mice
  • Up-Regulation / drug effects


  • Acetates
  • Histones
  • Lipids
  • Acetyl Coenzyme A
  • ATP Citrate (pro-S)-Lyase
  • ACSS2 protein, mouse
  • Acetate-CoA Ligase
  • Glucose