A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids

Fatty acids are the main structural and energy sources of the human body. W ithin the organism, they are presented to cells as fatty acid:albumin compl exes. Dissociation from albumin represents the first step of the cellular u ptake process, involving membrane proteins with high affinity for fatty aci ds, e.g., fatty acid translocase (FAT/CD 36) or the membrane fatty acid-bin ding protein (FABP(pm)). According to the thus created transmembrane concen tration gradient, uncharged fatty acids can flip-flop from the outer leafle t across the phospholipid bi layer. At the cytosolic surface of the plasma membrane, fatty acids can associate with the cytosolic FABP (FABP(c)) or wi th caveolin-1. Caveolins are constituents of caveolae, which are proposed t o serve as lipid delivery vehicles for subcellular organelles. It is not kn own whether protein (FABP(c))- and lipid (caveolae)-mediated intracellular trafficking of fatty acids operates in conjunction or in parallel. Channeli ng fatty acids to the different metabolic pathways requires activation to a cyl-CoA. For this process, the family of fatty acid transport proteins (FAT P 1-5/6) might be relevant because they have been shown to possess acyl-CoA synthetase activity. Their variable N-terminal signaling sequences suggest that they might be targeted to specific organelles by anchoring in the pho spholipid bi layer of the different subcellular membranes. At the highly co nserved cytosolic AMP-binding site of FATP, fatty acids are activated to ac yl-CoA for subsequent metabolic disposition by specific organelles. Overall , fatty acid uptake represents a continuous flow involving the following: d issociation from albumin by membrane proteins with high affinity for fatty acids; passive flip-flop across the phospholipid bilayer; binding to FABP(c ) and caveolin-1 at the cytosolic plasma membrane; and intracellular traffi cking via FABP(c) and/or caveolae to sites of metabolic disposition. The up take process is terminated after activation to acyl-CoA by the members of t he FATP family targeted intracellularly to different organelles.