**2.3 OSBPL1B (ORP1L)**

**Structure, Tissue distribution and Intracellular localization:** ORP1L belongs to the subfamily II of OSBP/ORP homologues. ORP1L has an ORD, an FFAT motif, a PH domain and three ankyrin repeats.

While macrophages, brain, and lung are the areas where ORP1L is expressed most predominantly, it is also found in colon, kidney, and liver (Johansson, Bocher et al. 2003). ORP1L localizes to late endosomes.

**Molecular functions related to dyslipidemia:** Johansson et al. reported that ORP1L binds to Rab7, modifies its functional cycle, and can interfere with LE/lysosome organization and endocytic membrane trafficking (Johansson, Lehto et al. 2005).

They show that the GTPase Rab7, when bound to GTP, simultaneously binds to ORP1L and RILP to form a RILP-Rab7-ORP1L complex, which is required for the perinuclear localization of late endosomes/lysosomes (Johansson, Rocha et al. 2007). The later study of Rocha et al., went deeper in examining these processes more in detail. They found that the cholesterol levels in late endosomes are sensed by ORP1L and are lower in peripheral vesicles. Under low cholesterol conditions, ORP1L conformation induces the formation of endoplasmic reticulum (ER)- late endosome membrane contact sites. At these sites, the ER protein VAP (VAMP [vesicle-associated membrane protein]-associated ER protein) can interact in trans with the Rab7-RILP complex to remove p150 (Glued) and associated motors. late endosomes then move to the microtubule plus end. Under high cholesterol conditions, as in Niemann-Pick type C disease, this process is prevented, and late endosomes accumulate at the microtubule minus end as the result of dynein motor activity. These data explain how the ER and cholesterol control the association of late endosomes with motor proteins and their positioning in cells (Rocha, Kuijl et al. 2009).

Recently, Vihervaara et al. have shown that ORP1L silencing in macrophage foam cells inhibits the efflux of lipoprotein-derived endocytosed cholesterol to apolipoprotein A-I, providing evidence for the involvement of ORP1L in both protein and lipid transport functions of the late endocytic compartments (Vihervaara, Uronen et al. 2011).

The multivesicular body(MVB) sorting pathway is known to be involved in many processes, including growth factor receptor down-regulation, exosome secretion, antigen presentation, the budding of enveloped viruses, and cytokinesis. Recently, Kobuna et al. have shown that knockdown of ORP1L induces the formation of enlarged MVBs in HeLa cells. They suggest that the proper cholesterol level of late endosomes/lysosomes generated by ORPs is required for normal MVB formation and MVB–mediated membrane protein degradation (Kobuna, Inoue et al. 2010).

**Epidemiological study:** Epidemiological study of ORP1L is not reported yet.
