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Zhao S , Torres A , Henry RA , Trefely S , Wallace M , Lee JV , Carrer A , Sengupta A , Campbell SL , Kuo YM , Frey AJ , Meurs N , Viola JM , Blair IA , Weljie AM , Metallo CM , Snyder NW , Andrews AJ , Wellen KE
ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch
Cell Rep. 2016 Oct 18;17(4) :1037-1052
PMID: 27760311    PMCID: PMC5175409    URL: https://www.ncbi.nlm.nih.gov/pubmed/27760311
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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.
Notes
2211-1247 Zhao, Steven Torres, AnnMarie Henry, Ryan A Trefely, Sophie Wallace, Martina Lee, Joyce V Carrer, Alessandro Sengupta, Arjun Campbell, Sydney L Kuo, Yin-Ming Frey, Alexander J Meurs, Noah Viola, John M Blair, Ian A Weljie, Aalim M Metallo, Christian M Snyder, Nathaniel W Andrews, Andrew J Wellen, Kathryn E Journal article United States Cell Rep. 2016 Oct 18;17(4):1037-1052. doi: 10.1016/j.celrep.2016.09.069.