Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition

Daniel K Glatzel,Andreas Koeberle,Helmut Pein,Konstantin Löser,Anna Stark,Nelli Keksel,Oliver Werz,Rolf Müller,Iris Bischoff,Robert Fürst

doi:10.1194/jlr.m080101

Abstract

The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. In recent years, ACC has been recognized as a promising drug target for treating different diseases. However, the role of ACC in vascular endothelial cells (ECs) has been neglected so far. To characterize the role of ACC, we used the ACC inhibitor, soraphen A, as a chemical tool, and also a gene silencing approach. We found that ACC1 was the predominant isoform in human umbilical vein ECs as well as in human microvascular ECs and that soraphen A reduced the levels of malonyl-CoA. We revealed that ACC inhibition shifted the lipid composition of EC membranes. Accordingly, membrane fluidity, filopodia formation, and migratory capacity were reduced. The antimigratory action of soraphen A depended on an increase in the cellular proportion of PUFAs and, most importantly, on a decreased level of phosphatidylglycerol. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.

Highlights

The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism
ACC1 and ACC2 levels in human umbilical vein endothelial cell (HUVEC) and human microvascular endothelial cell (HMEC) were compared with the human liver cancer cell line, HepG2, by quantitative PCR (qPCR) and Western blot analysis
The results of the immunoblotting experiments (Fig. 1D) were in accordance with these data. These results clearly show that ACC1 is the predominant isoform in endothelial cell (EC)

Summary

Introduction

The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.—Glatzel, D. Cytosolic ACC1 generates malonyl-CoA for de novo lipogenesis, while mitochondrial ACC2 generates malonyl-CoA that acts as an inhibitor of carnitine palmitoyltransferase This enzyme transfers fatty acids into the mitochondria for -oxidation to acetyl-CoA [16, 17]. The multi-domain enzyme acetyl-CoA carboxylase (ACC) is crucially involved in the fatty acid metabolism of eukaryotes.

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Conclusion