OSBP-related proteins: lipid sensors or transporters?

Protein families characterized by a ligand-binding domain homologous to that of oxysterol binding protein (OSBP) are present in eukaryotes ranging from yeast to man. The OSBP-related proteins (ORP) have been implicated in the regulation of various cellular functions. However, their exact mechanisms of action remain elusive, and it is evident that any single model for their function is insufficient. Recent data from our, and other laboratories, suggest that a unifying theme may be the binding of sterol ligands. Work with the yeast Saccharomyces cerevisiae suggests a function for ORPs in the nonvesicular transport of sterols. It is unclear whether this could also apply to mammals having a larger number of ORP genes that encode a variety of structurally complex ORP proteins. The existing evidence on mammalian ORP function points in many different directions, such as integration of sterol and sphingomyelin metabolism, regulation of neutral lipid metabolism, control of signaling cascades and regulation of the microtubule-based motility of endosomes/lysosomes. We envision that the mammalian ORPs mainly act as sterol sensors that relay information to a spectrum of cellular processes, including the central regulatory circuits of lipid metabolism.