ORP1L, ORP1S, and ORP2: Lipid Sensors and Transporters

Lipid transfer proteins are crucial for intracellular cholesterol trafficking at sites of membrane contact. In the OSBP/ORPs (oxysterol binding protein and OSBP-related proteins) family of lipid transfer proteins, ORP1L, ORP1S and ORP2 play important roles in cholesterol transport. ORP1L is an endosome/lysosome-anchored cholesterol sensor which may also move cholesterol bidirectionally at the interface between the endoplasmic reticulum and the endosome/lysosome. ORP2 delivers cholesterol to the plasma membrane, driven by PI(4,5)P2 hydrolysis. ORP1S may also transport cholesterol to the plasma membrane, although it is unclear if phosphoinositides are involved. The source of cholesterol delivered to the plasma membrane by ORP1S and ORP2 remains unclear. This review summarises the roles of these proteins in maintaining cellular cholesterol homeostasis and in human disease.

Comment on ‘Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol’

The plasma membrane in mammalian cells is rich in cholesterol, but how the cholesterol is partitioned between the two leaflets of the plasma membrane remains a matter of debate. Recently, Liu et al. used domain 4 (D4) of perfringolysin O as a cholesterol sensor to argue that cholesterol is mostly in the exofacial leaflet (<xref ref-type="bibr" rid="bib7">Liu et al., 2017</xref>). This conclusion was made by interpreting D4 binding in live cells using in vitro calibrations with liposomes. However, liposomes may be unfaithful in mimicking the plasma membrane, as we demonstrate here. Also, D4 binding is highly sensitive to the presence of cytosolic proteins. In addition, we find that a D4 variant, which requires >35 mol% cholesterol to bind to liposomes in vitro, does in fact bind to the cytoplasmic leaflet of the plasma membrane in a cholesterol-dependent manner. Thus, we believe, based on the current evidence, that it is unlikely that there is a significantly higher proportion of cholesterol in the exofacial leaflet of the plasma membrane compared to the cytosolic leaflet.

PPARs in Neurodegenerative and Neuroinflammatory Pathways

Background: PPARs are lipid sensors activated by dietary lipids or their metabolites, mainly fatty acids and eicosanoids, that play critical roles in CNS biology, since brain has a very high lipid content and has the higher energetic metabolism in the body. Methods: In neurodegenerative diseases in addition to metabolic impairment, also neuroinflammation is observed and PPARs are also closely linked to inflammatory processes. Several studies have revealed a complicated relationship between the innate immune response and tissue metabolism. Results: In the brain, during pathological conditions, an alteration in metabolic status occurs, particularly involving glucose utilization and production, a condition which is generally related to metabolic changes. Conclusion: Taking into account the high expression of PPARs in the brain, this review will focus on the role of these transcription factors in CNS diseases.