biostudies-literature00470Zhao SNICHD NIH HHSNIEHS NIH HHSNCI NIH HHSNIGMS NIH HHS1037-1052https://www.ebi.ac.uk/biostudies/studies/S-EPMC5175409biostudies-literatureUnknown17(4)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.Cell reportsATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch.PMC5175409P30 CA016520P30 ES013508T32 CA115299K22 ES026235R21 HD087866K12 GM081259R01 CA188652R01 GM102503P30 CA006927R01 CA174761F31 CA189744Campbell SLWallace MCarrer AWellen KETrefely SAndrews AJBlair IAViola JMHenry RAFrey AJMetallo CMLee JVSengupta AKuo YMMeurs NZhao SWeljie AMSnyder NWTorres A47falseATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch.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.2016-01-01T00:00:00Z2016 Oct2020-10-31T09:11:06Z2019-03-27T02:32:12ZS-EPMC51754092776031110.1016/j.celrep.2016.09.069