Oxysterol‐binding proteins–emerging roles in cell regulation

Abstract

Cytoplasmic oxysterol-binding protein homologues, designated OSBP-like (OSBPL) or OSBP-related (ORP) proteins, constitute a family of lipid binding/transfer proteins present in a wide spectrum of eukaryotes. In mammals these proteins are encoded by 12 genes expressed ubiquitously but at different quantities in different tissue and cell types. Their unifying feature is a b-barrel-like ligand-binding domain that has been shown to accommodate sterol ligands: oxysterols, cholesterol, or both, while a recent report shows that also phospholipid can be bound. Certain family members have the capacity to mediate or facilitate intracellular sterol transport or lipid exchange, while others are implicated as sterol sensors involved in cell regulation: lipid homeostatic control, signal transduction, organelle motility, or vesicle transport. Several ORPs have been localized to membrane contact sites, at which endoplasmic reticulum membranes are closely apposed with other organelles-indicating functions in the nonvesicular transport of ions or small molecules, or in regulation of enzymatic components active at the contact sites. OSBPL gene polymorphisms are associated with cardiovascular risk factors, and altered ORP expression levels occur in certain cancers, providing the first indications of ORP involvement in human disease. In this review we summarize and analyze the latest findings concerning the function of OSBPL/ORP proteins.

The Role of Oxysterols in Human Cancer

“…The OSBP family also plays roles also in other cellular processes, such as vesicular trafficking [88, 89]. OSPBs also act as scaffolds in cell signaling pathways, or participate in cytoskeleton organization and cell adhesion [11, 88].…”

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

“…4,14 However, the functions of oxysterols are not limited to their LXR binding, 15 but they significantly interact with other cellular proteins, giving rise to different effects. Examples of proteins affected by oxysterols are: a) insulin-induced gene (INSIG) proteins, regulating the function of sterol response element binding protein (SREBP); 16 b) Niemann-Pick C1 (NPC1) and oxysterol-binding protein family (OSBP/ORP), involved in cholesterol metabolism; 17 and c) Smoothened oncoprotein, interfering with the Hedgehog signalling. 18 So far the oxysterol medicinal chemistry has been mainly focused on the identification of LXR modulators, although the number of the studied natural and synthetic oxysterol derivatives is only marginal when compared to that of the non-steroidal ligands.…”

“…However, the functions of oxysterols are not limited to their LXR binding, but they significantly interact with other cellular proteins, giving rise to different effects. Examples of proteins affected by oxysterols are (a) insulin-induced gene (INSIG) proteins, regulating the function of sterol response element binding protein (SREBP); (b) Niemann-Pick C1 (NPC1) and oxysterol-binding protein family (OSBP/ORP), involved in cholesterol metabolism; and (c) smoothened oncoprotein, interfering with the Hedgehog signaling …”

OSBP-Related Proteins (ORPs) in Human Adipose Depots and Cultured Adipocytes: Evidence for Impacts on the Adipocyte Phenotype

“…Moreover, OSBP has the capacity to regulate the insulin induction of SREBP-1c and hepatic lipogenesis [27] . The ORP protein/gene family in humans and mice consists of a large number of proteins encoded by 12 genes, which serve diverse functions in cellular lipid metabolism and signaling [28] – [30] . Several members of the ORP family have been putatively connected with metabolic diseases: ORP8 was suggested to regulate insulin signaling in mouse models of obesity [31] and lipid levels in mouse plasma and liver tissue [32] .…”