Rosiglitazone Inhibits Acyl-CoA Synthetase Activity and Fatty Acid Partitioning to Diacylglycerol and Triacylglycerol via a Peroxisome Proliferator–Activated Receptor-γ–Independent Mechanism in Human Arterial Smooth Muscle Cells and Macrophages

Abstract

Rosiglitazone is an insulin-sensitizing agent that has recently been shown to exert beneficial effects on atherosclerosis. In addition to peroxisome proliferator-activated receptor (PPAR)-␥, rosiglitazone can affect other targets, such as directly inhibiting recombinant long-chain acylCoA synthetase (ACSL)-4 activity. Because it is unknown if ACSL4 is expressed in vascular cells involved in atherosclerosis, we investigated the ability of rosiglitazone to inhibit ACSL activity and fatty acid partitioning in human and murine arterial smooth muscle cells (SMCs) and macrophages. Human and murine SMCs and human macrophages expressed Acsl4, and rosiglitazone inhibited Acsl activity in these cells. Furthermore, rosiglitazone acutely inhibited partitioning of fatty acids into phospholipids in human SMCs and inhibited fatty acid partitioning into diacylglycerol and triacylglycerol in human SMCs and macrophages through a PPAR-␥-independent mechanism. Conversely, murine macrophages did not express ACSL4, and rosiglitazone did not inhibit ACSL activity in these cells, nor did it affect acute fatty acid partitioning into cellular lipids. Thus, rosiglitazone inhibits ACSL activity and fatty acid partitioning in human and murine SMCs and in human macrophages through a PPAR-␥-independent mechanism likely to be mediated by ACSL4 inhibition. Therefore, rosiglitazone might alter the biological effects of fatty acids in these cells and in atherosclerosis.

Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells

“…We have previously shown that ACSL4 is one of the ACSL isoforms expressed in human arterial SMCs ( 17 ). These cells also express ACSL1, ACSL3, and ACSL5 ( 17 ).…”

Fatty Acid CoA Ligase-4 Gene Polymorphism Influences Fatty Acid Metabolism in Metabolic Syndrome, but not in Depression

“…diacylglycerol (DAG), have been shown to interfere with insulin signaling in skeletal muscle and liver, while in β -cells of pancreas the increased content of ceramide and other lipid metabolites is associated with β -cell apoptosis (Manco et al 2004). FACL4 is involved in de novo synthesis of DAG and FA storage in TG and FACL1 and/or FACL3 have additional effects on FA partitioning into phospholipids (Askari et al 2007).…”

“…Rosiglitazone, which is an insulin-sensitizer, inhibits FACL4 and concomitantly increases activity of stearoyl-CoA desaturase (SCD) and adenosine monophosphate kinase (Evans et al 2004;Boyle et al 2008), was shown to inhibit FA partitioning into DAG and TG in human smooth muscle cells (SMC) and macrophages and only transiently inhibit partitioning of oleic acid into PL in human SMC, through a PPARγ independent mechanism (Askari et al 2007). In only one study, plasma FA in TG after rosiglitazone treatment was assessed in a small group of type 2 diabetics and SCD and Δ 5 but not Δ 6 desaturases activity indexes were increased .…”

“…The FACL4 isoform, located in mitochondrial associated membrane and on the peroxisomal membrane, prefers AA and EPA as substrate. It is mainly expressed in the steroidogenic tissues but also in neuronal and smooth muscle cells (Kang et al 1997;Cao et al 1998;Coleman et al 2002;Askari et al 2007). The FACL4 gene is mapped to the long arm of human chromosome X, region q23 (Cao et al 1998).…”

Effect of the non-steroidal anti-inflammatory drugs on the acyl-CoA synthetase activity toward medium-chain, long-chain and polyunsaturated fatty acids in mitochondria of mouse liver and brain

“…On the other hand, the long-chain acylCoA synthetases for palmitic acid were inhibited by salicylic acid 20,21,25 , diclofenac 20 , ibuprofen 26 , ketoprofen 26 , naproxen 26 , rosiglitazone 27 , thiazolidinediones 28 and troglitazone 29 . Further, arachidonic acid (AA) metabolism in brain has been reported to be a target of valproic acid 30 .…”