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A more recent version of this article appeared on March 1, 2003
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Submitted on August 5, 2002
Revised on November 7, 2002
Accepted on November 22, 2002
1 Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O. Box 104, FIN-00251, Helsinki, Finland
2 Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II-U545 INSERM, 1 rue Calmette, BP 245, 59019 Lille cedex, France
3 Department of Biosciences, Division of Biochemistry, Viikki Biocenter, Viikinkaari 5, FIN-00014 University of Helsinki, Finland
* Corresponding author. E-mail address: vesa.olkkonen{at}ktl.fi.
Oxysterol binding protein (OSBP) homologues comprise a family of 12 proteins in humans (Jaworski et al., 2001; Lehto et al., 2001). Two variants of OSBP-related protein (ORP) 1 have been identified, a short one that consists of the carboxy-terminal ligand binding domain only (ORP1S, 437 aa) and a longer N-terminally extended form (ORP1L, 950 aa) encompassing three ankyrin repeats and a pleckstrin homology (PH) domain. We now report that the two mRNAs show marked differences in tissue expression. ORP1S predominates in skeletal muscle and heart, while ORP1L is the most abundant form in brain and lung. Upon differentiation of primary human monocytes into macrophages, both ORP1S and ORP1L mRNAs were induced, the upregulation of ORP1L being over 100-fold. The intracellular localization of the two ORP1 variants was found to be different. While ORP1S is largely cytosolic the ORP1L variant localizes to late endosomes. A significant amount of ORP1S but only little ORP1L was found in the nucleus. The ORP1L ankyrin repeat (ANK) region (aa 1-237) was found to localize to late endosomes like the full length protein. This localization was even more pronounced for a fragment which additionally includes the PH domain (aa 1-408). The amino-terminal region of ORP1L consisting of the ANK and PH domains is therefore likely to be responsible for the targeting of ORP1L to late endosomes. Interestingly, overexpression of ORP1L was found to enhance the LXR
-mediated transactivation of a reporter gene, while ORP1S failed to influence this process. The results suggest that the two forms of ORP1 are functionally distinct and that ORP1L is involved in control of cellular lipid metabolism.
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