Is membrane transport of FFA mediated by lipid, protein, or both? Mechanisms and regulation of protein-mediated cellular fatty acid uptake: molecular, biochemical, and physiological evidence.

Jan F. C. Glatz Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands Fatty acids serve as substrates for diverse cellular processes, including membrane biosynthesis, protein modification, regulation of transcription, intracellular signaling, and energy provision for tissues such as liver, heart, and skeletal muscle. Although these processes are highly regulated, it has long been thought that entry of long-chain fatty acids into parenchymal cells occurs in an unregulated manner by diffusion (57–60). However, from a physiological perspective, it may be speculated that it would be highly desirable to regulate the entry of fatty acids into the cell, given their important roles in many key cellular processes. In addition, since fatty acids may exert harmful effects, related to their detergent-like action (114, 122), such detrimental effects could be better controlled if fatty acid entry into the cell was regulated. In recent years, there has been considerable debate as to whether fatty acid is transported into cells or diffuses rapidly into the cell. It now appears that this debate is less strident, as it has been acknowledged recently that evidence supporting passive diffusion as the main mechanism for fatty acid uptake is apparently in error, since “previous reports for rapid flip-flop were based on an incorrect interpretation of the measurements” (79), Because of this (79) and other experiments (78), it has been concluded that “the lipid bilayer portion of biological membranes may present a significant barrier to transport of FFA across cell membranes” (36) and that “flip-flop is the rate limiting step for FFA transport across lipid vesicles” (78). Furthermore, “this implies that at least certain biological membranes may require protein-mediated transporters to catalyze the flip-flop step” (78). Since we (13, 27–29, 73, 97, 98, 100) and others (32, 45, 54) have previously provided considerable support for the protein-mediated entry of long-chain fatty acids into the cell, especially in metabolically important tissues such as heart and skeletal muscle, we concur with these recent conclusions (36, 78, 79) that (membrane-associated) proteins are involved in cellular fatty acid uptake. Indeed, very solid evidence, based on physiological, biochemical, molecular, and genetic studies, supports the idea that fatty acid entry into many tissues occurs via a proteinmediated mechanism that is highly regulatable both acutely (within minutes) and