Flip-flop: The transmembrane translocation of lipids

Abstract

Christopher F. Higgins Imperial Cancer Research Fund Laboratories Institute of Molecular Medicine and Nuffield Department of Clinical Biochemistry University of Oxford John Radcliffe Hospital Oxford OX3 9DU England introduction Many of us, as students, were instilled with the prejudice that lipids are biologically uninteresting, forming a rela- tively inert barrier that surrounds cells and organelles. Nothing could be further from the truth. Fatty acids, phos- pholipids, and their derivatives are active participants in a wide spectrum of cellular processes such as signaling, exo- and endocytosis, and cell growth. Even as the major structural component of the cell membrane, phospholipids are not inert: lipid composition has a significant influence on the activities of many membrane proteins, such as those involved in transport and transmembrane signaling. It has, of course, been known for many years that lipid compositions differ among membranes and that the distri- bution of lipids between the two leaflets of the bilayer is often highly asymmetric. Such observations, in them- selves, illustrate the importance of lipid composition: why would the cell go to the trouble of maintaining such asym- metries without good reason? Defects in lipid metabolism are also associated with many clinical disorders, including cardiac and skeletal myopathies, neurological disfunc- tions, and inherited syndromes such as adrenoleukodys- trophy (of Lorenzo’ s Oil fame). One aspect of lipid metabolism that has received rela- tively little attention is how lipids get to where they are supposed to be within the cell. How do extracellular fatty acids reach the subcellular compartments in which they are metabolized? How are phospholipids excreted from