Lipid transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sites.

The endoplasmic reticulum (ER) is the main center for the synthesis of various lipid types in cells, and newly synthesized lipids are delivered from the ER to other organelles. In the past decade, various lipid transfer proteins (LTPs) have been recognized as mediators of lipid transport from the ER to other organelles; inter-organelle transport occurs at membrane contact sites (MCSs) and in a nonvesicular manner. Although the intermembrane transfer reaction catalyzed by LTPs is an equilibrium reaction, various types of newly synthesized lipids are transported unidirectionally in cells. This review provides a brief history of the inter-organelle trafficking of lipids and summarizes the structural and biochemical characteristics of the ceramide transport protein (CERT) as a typical LTP acting at MCSs. In addition, this review compares several LTP-mediated inter-organelle lipid trafficking systems and proposes that LTPs generate unidirectional fluxes of specific lipids between different organelles by indirect coupling with the metabolic reactions that occur in specific organelles. Moreover, the available data also suggest that the major advantage of LTP-mediated lipid transport at MCSs may be the accuracy of delivery. Finally, how cholesterol is enriched in the plasma membrane is discussed from a thermodynamic perspective.