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

Abstract

SUMMARY Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-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.

De novo acetate production is coupled to central carbon metabolism in mammals

“…ATP citrate lyase (ACLY) is a cytosolic enzyme that converts nucleocytosolic citrate to Ac-CoA and acetate requirements in cells increase when its activity is impaired 33 . We thus considered mouse embryonic fibroblasts (MEFs), known to produce low amounts of acetate (Fig 1c) that were engineered to lack ACLY (ACLY KO) ( Fig.…”

“…We thus considered mouse embryonic fibroblasts (MEFs), known to produce low amounts of acetate (Fig 1c) that were engineered to lack ACLY (ACLY KO) ( Fig. 5a and 5b) that were previously described and further confirmed to exhibit an acquired dependence on acetate 33 . Coculturing these MEFs with acetate-producing HCT116 cells separated by a 0.4 micron membrane allowing for free diffusion (Fig.…”

“…MEF (ACLY WT (Aclyf/f) and KO) cells were prepared as described previously 33 . HCT116, SKOV3, HepG2, and BT474 cell lines were obtained from ATCC.…”

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

“…Mitochondrial acetyl-CoA cannot directly cross the mitochondrial membrane but, instead, is transferred to the cytosol via citrate export and conversion to acetyl-CoA by ATP citrate-lyase (ACLY) (6). ACLY has been shown to regulate histone acetylation levels and influence gene regulation in diverse mammalian cell types (19,21,(27)(28)(29), and histone acetylation is responsive to glucose availability in an ACLY-dependent manner (19,21,30). We have shown previously that Acly silencing impairs histone acetylation and expression of select genes such as Glut4 during 3T3-L1 adipocyte differentiation (18).…”

“…We have shown previously that Acly silencing impairs histone acetylation and expression of select genes such as Glut4 during 3T3-L1 adipocyte differentiation (18). More recently, we have reported the generation of mice lacking ACLY in adipose tissue (Acly FATϪ/Ϫ mice), which exhibit normal body weight and adipose tissue architecture but reduced expression of Glut4 and lower acetylation of some histone tail lysines (30). ACLY is highly regulated by dietary conditions; its expression is induced by high carbohydrate exposure and suppressed upon high-fat feeding (31)(32)(33)(34).…”