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. Within the organism, they are presented to cells as fatty acid:albumin complexes. Dissociation from albumin represents the first step of the cellular uptake process, involving membrane proteins with high affinity for fatty acids, e.g., fatty acid translocase (FAT/CD 36) or the membrane fatty acid-binding protein (FABPpm). According to the thus created transmembrane concentration gradient, uncharged fatty acids can flip-flop from the outer leaflet across the phospholipid bilayer. At the cytosolic surface of the plasma membrane, fatty acids can associate with the cytosolic FABP (FABP(c)) or with caveolin-1. Caveolins are constituents of caveolae, which are proposed to serve as lipid delivery vehicles for subcellular organelles. It is not known whether protein (FABP(c))- and lipid (caveolae)-mediated intracellular trafficking of fatty acids operates in conjunction or in parallel. Channeling fatty acids to the different metabolic pathways requires activation to acyl-CoA. For this process, the family of fatty acid transport proteins (FATP 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 phospholipid bilayer of the different subcellular membranes. At the highly conserved cytosolic AMP-binding site of FATP, fatty acids are activated to acyl-CoA for subsequent metabolic disposition by specific organelles. Overall, fatty acid uptake represents a continuous flow involving the following: dissociation 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 trafficking via FABP(c) and/or caveolae to sites of metabolic disposition. The uptake process is terminated after activation to acyl-CoA by the members of the FATP family targeted intracellularly to different organelles.
Stremmel
W
W
Department of Gastroenterology, Ruprecht-Karls-University, 69115 Heidelberg, Germany. wolfgang_stremmel@med.uni-heidelberg.de
Pohl
L
L
Ring
A
A
Herrmann
T
T
D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens; D002352:Carrier Proteins / Q000378:metabolism*; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D050612:Fatty Acid Transport Proteins; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D015388:Organelles / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C495540:CAV1 protein, human; D018955:CD36 Antigens; D002352:Carrier Proteins; D051242:Caveolin 1; D022461:Caveolins; C107608:FABP7 protein, human; D050612:Fatty Acid Transport Proteins; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C493568:SLC27A1 protein, human; C493573:SLC27A6 protein, human; D025521:Tumor Suppressor Proteins