Inhibition of ATP citrate lyase induces triglyceride accumulation with altered fatty acid composition in cancer cells

Abstract

De novo lipogenesis is activated in most cancers and several lipogenic enzymes have been implicated as therapeutic targets. Here, we demonstrate a novel function of the lipogenic enzyme, ATP citrate lyase (ACLY), in lipid metabolism in cancer cells. ACLY depletion by small interfering RNAs caused growth suppression and/or apoptosis in a subset of cancer cell lines. To investigate the effect of ACLY inhibition on lipid metabolism, metabolome and transcriptome analysis was performed. ACLY depletion blocks the fatty acid chain elongation from C16 to C18 in triglyceride (TG), but not in other lipid classes. Meanwhile, wild-type ACLY overexpression enhanced fatty acid elongation of TG, whereas an inactive mutant ACLY did not change it. ACLY depletion-mediated blockade of fatty acid elongation was coincident with downregulation of long-chain fatty acid elongase ELOVL6, which resides in endoplasmic reticulum (ER). Paradoxically, ACLY depletion-mediated growth suppression was associated with TG accumulation. ACLY depletion downregulated the expression of carnitine palmitoyltransferase 1A, which is a mitochondrial fatty acid transporter. Consistent with this finding, metabolome analysis revealed that ACLY positively regulates the carnitine system, which plays as an essential cofactor for fatty acid transport across mitochondrial membrane. AICAR, an activator of mitochondrial fatty acid oxidation (FAO), significantly reduced ACLY depletion-mediated TG accumulation. These data indicate that inhibition of ACLY might affect both fatty acid elongation in ER and FAO in mitochondria, thereby explaining the TG accumulation with altered fatty acid composition. This phenotype may be a hallmark of growth suppression mediated by ACLY inhibition.Most malignant cells exhibit elevated lipogenesis and generate lipids independently of extracellular fatty acids levels. Fatty acids and cholesterols are likely to be utilized for membrane composition, protein modification and signal transduction as a second messenger, all of which are crucial for cell survival, proliferation and transformation in cancer cells. [1][2][3][4][5] Because cancer cells adapt to and depend on specific metabolisms for their survival, blocking the accelerated metabolic flux may be a feasible strategy for cancer therapy.De novo fatty acids (i.e., palmitate) are synthesized in the cytoplasm; however, other types of fatty acids are generated and modified in other organelle, such as endoplasmic reticulum (ER). Fatty acid chain elongation and desaturation are catalyzed by the specific enzymes in ER. Especially when glucose availability is limited, fatty acids are oxidized in mitochondria or peroxisome and are utilized for energy production. Increasing evidence shows that fatty acid oxidation (FAO) in mitochondria is important for the cell survivals even in cancer cells. 6,7 Thus, quantity and species of fatty acids are regulated and orchestrated through fatty acid synthesis, modification and degradation in different subcellular compartments. ATP citrate lyase (ACLY) plays...

Genome-wide mRNA-seq profiling reveals predominant down-regulation of lipid metabolic processes in adipose tissues of Small Tail Han than Dorset sheep

“…A total of 12 differential genes were enriched in this process, of which 11 genes were down-regulated and the 12th gene, glycerol kinase (GK), was up- regulated. Some of the 12 dys-regulated genes have been implicated in association to the excess fat deposition observed in Han sheep, as studied by others [11,15,23]. For instance, Migita et al reported that inhibition of ATP citrate lyase(ACLY) might affect both fatty acid elongation in endoplasmic reticulum and fatty acid oxidation in mitochondria, thereby explaining the triglyceride accumulation with altered fatty acid composition [23].…”

Elovl6 is a poor prognostic predictor in breast cancer

“…Among the enzymes involved in de novo lipogenesis, inhibition of ATP citrate lyase (ACLY) results in apoptosis and growth suppression in human cancer cells (34). In addition, ACLY depletion induces phosphorylation of AMP-activated protein kinase and coincides with Elov16 downregulation (35). Notably, it was reported that diethylnitrosamine-induced carcinogenesis, which mimics inflammatory events in early hepatocarcinogenesis, increased C18/C16 ratio and hepatic lipids.…”

Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells

“…ACLY is at the center of this metabolic shift, transferring metabolites from glycolysis to lipid synthesis using cytosolic citrate as its substrate and precursor (41). Enhanced activity or expression of ACLY has been documented in a number of cancers, making this enzyme an attractive therapeutic target with a number of selective inhibitors in development displaying anticancer property in both cell lines and animal models (29,42).…”