Family of human oxysterol binding protein (OSBP) homologues: a novel member implicated in brain sterol metabolism

Saara Laitinen,Vesa M Olkkonen,Christian Ehnholm,Elina Ikonen

doi:10.1016/s0022-2275(20)32095-2

Saara Laitinen, Vesa M Olkkonen + Show 2 more

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https://doi.org/10.1016/s0022-2275(20)32095-2

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Abstract

Oxysterol binding protein (OSBP) is a cytosolic protein that undergoes ligand-induced binding to the Golgi apparatus and has been implicated in the regulation of cellular cholesterol metabolism. In the yeast Saccharomyces cerevisiae an OSBP homologue is involved in membrane trafficking through the Golgi complex. Prompted by the multitude of OSBP-related genes in the yeast genome, we carried out a search for human expressed sequence tags (ESTs) displaying homology to the sterol-binding domain of OSBP. This revealed a minimum of six novel OSBP-related proteins, designated ORP-1 to ORP-6. ORP cDNA probes were generated by reverse transcription-PCR from human liver mRNA, and used for Northern blot analysis of human tissue transcript panels. This verified that each of them represents a different gene product and showed that they display distinct tissue-specific expression patterns. The ORP-1 and -2 mRNA expression levels were similar to or higher than that of OSBP while the ORP-3 to -6 mRNAs were detected at lower levels in specific tissues.▪ The most abundantly expressed new gene, ORP-1, was transcribed at strikingly high levels in the cortical areas of human brain and displayed sterol-regulated expression in a cultured human neuroblastoma cell line. This indicates that ORP-1 may play an important role in maintaining the sterol balance in cells of the central nervous system. Together with OSBP, the identified gene products constitute a novel human protein family that may provide a link between organellar sterol status and membrane dynamics.—Laitinen, S., V. M. Olkkonen, C. Ehnholm, and E. Ikonen. Family of human oxysterol binding protein (OSBP) homologues: a novel member implicated in brain sterol metabolism.

Highlights

Oxysterol binding protein (OSBP) is a cytosolic protein that undergoes ligand-induced binding to the Golgi apparatus and has been implicated in the regulation of cellular cholesterol metabolism
The C-terminal part of the protein is responsible for Abbreviations: OSBP, oxysterol binding protein; ORP, oxysterol binding protein-related protein; EST, expressed sequence tag; PCR, polymerase chain reaction; PH, pleckstrin homology; LDL, low density lipoprotein; FBS, fetal bovine serum; LPDS, lipoprotein-deficient serum; CNS, central nervous system
Among the long OSBP homologues the conservation was highest in the sterol binding domain (36 –39% identical residues, data not shown)

Summary

Introduction

Oxysterol binding protein (OSBP) is a cytosolic protein that undergoes ligand-induced binding to the Golgi apparatus and has been implicated in the regulation of cellular cholesterol metabolism. Oxygenated derivatives of cholesterol have multiple biological activities, including perturbation of cellular cholesterol homeostasis, disturbance of cellular membrane structure, and cytotoxic effects Because of their toxicity, oxysterols pose a potential threat to human health and have been suggested to promote atherosclerosis, aging, and cancer LXR was found to bind oxysterols that exist in the liver when there is a surplus of cholesterol and function as a ligand-activated transcription factor to up-regulate cholesterol catabolism to bile acids [4, 5] Another member of this family, PPAR␥, functions as a receptor for oxidized metabolites of cholesteryl esters and regulates macrophage gene expression upon uptake of oxidized low density lipoprotein (LDL) [6, 7].

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