The role of ATP citrate-lyase in the metabolic regulation of plasma lipids

Abstract

ATP citrate (pro-S)-lyase (EC 4.1.3.8), a cytosolic enzyme that generates acetyl-CoA for cholesterol and fatty acid synthesis de novo, is a potential target for hypolipidaemic intervention. Here we describe the biological effects of the inhibition of ATP citrate-lyase on lipid metabolism in Hep G2 cells, and plasma lipids in rats and dogs, by using SB-204990, the cell-penetrant gamma-lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076 (Ki=1 microM). Consistent with an important role of ATP citrate-lyase in the supply of acetyl-CoA units for lipid synthesis de novo, SB-204990 inhibited cholesterol synthesis and fatty acid synthesis in Hep G2 cells (dose-related inhibition of up to 91% and 82% respectively) and rats (76% and 39% respectively). SB-204990, when administered orally to rats, was absorbed into the systemic circulation; pharmacologically relevant concentrations of SB-201076 were recovered in the liver. When administered in the diet (0.05-0. 25%, w/w) for 1 week, SB-204990 caused a dose-related decrease in plasma cholesterol (by up to 46%) and triglyceride levels (by up to 80%) in rats. This hypolipidaemic effect could be explained, at least in part, by a decrease (up to 48%) in hepatic very-low-density lipoprotein (VLDL) production as measured by the accumulation of VLDL in plasma after injection of Triton WR-1339. SB-204990 (25 mg/kg per day) also decreased plasma cholesterol levels (by up to 23%) and triglyceride levels (by up to 38%) in the dog, preferentially decreasing low-density lipoprotein compared with high-density lipoprotein cholesterol levels. Overall these results are consistent with the concept that ATP citrate-lyase is an important enzyme in controlling substrate supply for lipid synthesis de novo and a potential enzyme target for hypolipidaemic intervention.

ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

“…We next investigated the effect of GSK165, which is a novel ACLy inhibitor modified from 2-hydroxy-N-phenylbenzenesulfonamide pharmacophore, structurally different from the known ACLy inhibitor SB-20499 and its pro-drug SB-201076 (24, 25). As shown in Figure 2C and D, GSK165 inhibited ACLy activity in a concentration-dependent manner and had a growth-inhibitory effect on cancer cells as a single agent with an IC 50 of ~30 µM.…”

“…ACLy activity was determined as described previously (24) in an assay mixture containing 100 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 , 20 mM K3Citrate, 1 mM dithiothreitol, 10 U of malic dehydrogenase, 300 µM coenzyme A (CoA), 280 µM NADH, and various amounts of purified ACLy (BPS Bioscience, San Diego, CA), and optimal conditions for measuring enzyme activities were identified. The reaction was initiated by adding 10 mM ATP at 37°C, and NADH oxidation, as evidenced by a decrease in absorbance at 340 nm, was monitored continuously for 10 min using a microplate reader.…”

Dietary acetic acid reduces serum cholesterol and triacylglycerols in rats fed a cholesterol-rich diet

“…Therefore, it is very likely that dietary acetic acid inhibits fatty acid synthesis through a decrease in SREBP-1 mRNA. Indeed, it should be noted that the activity of ATP-CL, which plays an important role in supplying acetyl-CoA to pathways of both cholesterogenesis and lipogenesis (Pearce et al 1998), was markedly reduced in the cholesterol and acetic acid diet group.…”

The Roles of Sterol Regulatory Element-binding Proteins in the Transactivation of the Rat ATP Citrate-Lyase Promoter

“…In liver and adipose tissue, this enzyme plays an important role in supplying acetyl-CoA for both fatty acid and cholesterol synthesis (2). As the specific inhibition of ACL in rats significantly decreases the plasma levels of triacylglycerol and cholesterol, ACL is expected to be a potential target for hypolipidemic intervention (3,4). The activity of ACL is mainly regulated at the level of transcription by diet regimen and insulin, like other lipogenic enzymes, such as fatty acid synthase and acetyl-CoA carboxylase (5).…”