Outlook: membrane junctions enable the metabolic trapping of fatty acids by intracellular acyl-CoA synthetases

Abstract

The mechanism of fatty acid uptake is of high interest for basic research and clinical interventions. Recently, we showed that mammalian long chain fatty acyl-CoA synthetases (ACS) are not only essential enzymes for lipid metabolism but are also involved in cellular fatty acid uptake. Overexpression, RNAi depletion or hormonal stimulation of ACS enzymes lead to corresponding changes of fatty acid uptake. Remarkably, ACS are not localized to the plasma membrane where fatty acids are entering the cell, but are found instead at the endoplasmic reticulum (ER) or other intracellular organelles like mitochondria and lipid droplets. This is in contrast to current models suggesting that ACS enzymes function in complex with transporters at the cell surface. Drawing on recent insights into non-vesicular lipid transport, we suggest a revised model for the cellular fatty acid uptake of mammalian cells which incorporates trafficking of fatty acids across membrane junctions. Intracellular ACS enzymes are then metabolically trapping fatty acids as acyl-CoA derivatives. These local decreases in fatty acid concentration will unbalance the equilibrium of fatty acids across the plasma membrane, and thus provide a driving force for fatty acid uptake.

Keywords: acyl-CoA synthetase; fatty acid uptake; lipid metabolism; membrane junctions; metabolic trapping.

Figure 1

Membrane junctions enable the metabolic trapping of fatty acids by intracellular acyl-CoA synthetases. Fatty acids from the extracellular space become integrated into the plasma membrane, which is likely facilitated by plasma membrane associated fatty acid binding proteins (light blue). Transport of fatty acids between the plasma membrane and the endoplasmic reticulum (and other intracellular organelles) may be organized by three different pathways. (A) Fatty acids diffuse spontaneously across the narrow membrane junction. (B) Cytosolic fatty acid binding proteins (dark green) may act as lipid chaperones to increase transport rates between different membranes. (C) Fatty acid transfer proteins (orange) may transport molecules by conformational changes rather than diffusion. Fatty acids delivered to the ER will rapidly equilibrate by lateral diffusion, and finally be esterified by acyl-CoA synthetases (ACS). An increase in ACS activity will lead to a relative depletion of fatty acids from the ER, and this change in the concentration gradient will be transmitted ultimately to the extracellular space, providing the driving force for fatty acid uptake. PM plasma membrane, ER endoplasmic reticulum, ACS acyl-CoA synthetase.