Exp Clin Endocrinol Diabetes 2012; 120 - A6
DOI: 10.1055/s-0032-1330800

Acyl-CoA synthetases in lipid metabolism and storage

M Poppelreuther 1, EM Küch 1, R Grossmann 1, C Du 1, F Ehehalt 1, S Staudacher 1, R Ehehalt 1, J Füllekrug 1
  • 1Molecular Cell Biology Laboratory Internal Medicine IV, University of Heidelberg, Germany

Lipid droplets are intracellular storage organelles which are implicated in obesity and the pathogenesis of metabolic diseases like atherosclerosis and diabetes type 2. They consist of a neutral lipid core surrounded by a phospholipid membrane containing specific proteins. Biosynthesis of neutral and membrane lipids as well as energy generation by ß-oxidation is enabled by the fatty acyl-CoA synthetase (ACS), a family of essential enzymes which activate fatty acids by esterification with coenzyme A. ACS enzymes are expressed simultaneously in a given cell type or tissue, but differences in expression, nutritional regulation, substrate specificity and subcellular localization suggest individual functions which however remain currently mostly undefined.

We have recently shown that two of the ACS enzymes (ACSL3 and ACSL4_v2) are localized at the lipid droplet surface, suggesting a function in the regulation of cellular neutral lipid storage. Fatty acids chemically activated by the ACS enzymes may enable the growth of lipid droplets by the local biosynthesis of triglycerides and phospholipids. Changing the expression levels of ACS enzymes by overexpression or RNAi leads to corresponding changes in cellular fatty acid uptake, indicating metabolic trapping by these intracellular enzymes. Furthermore, the homeostasis of phospholipid classes is changed when levels of ACS enzymes are manipulated. This is in line with the idea of fatty acid channeling into specific metabolic pathways by different ACS enzymes. We identified the FATP4 ACS as a novel target of insulin signaling in muscle cells, suggesting that acyl-CoA synthetases are also acutely regulated by hormonal stimulation.

Fatty acyl-CoA molecules and their lipid derivatives have long been implicated in the development of insulin resistance. In future work we will analyze the role of the ACS enzymes in these pathogenic processes, with the aim to find new therapeutic options for the prevention and treatment of diabetes type 2.