**2.7 OSBPL5 (ORP5)**

132 Dyslipidemia - From Prevention to Treatment

**Structure, Tissue distribution and Intracellular localization:** ORP3 belongs to the subfamily III of OSBP/ORP homologues. ORP3 has an ORD, a PH domain and an FFAT motif. A total of eight isoforms of ORP3 were demonstrated with alternative splicing (Collier, Gregorio-King et al. 2003). In human tissues there was specific isoform distribution, with most tissues expressing varied levels of isoforms with the complete ORD; while only whole brain, kidney, spleen, thymus, and thyroid expressed high levels of the isoforms associated with the truncated ORD. The expression in cerebellum, heart, and liver of most isoforms was negligible. Lehto et al described that ORP3 was expressed at high levels in kidney tubule epithelia and in the human embryonic kidney cell line HEK293 (Lehto,

They also described that the endogenous ORP3 protein in HEK293 cells localized at the ER

**Molecular functions related to dyslipidemia:** The direct evidence that ORP3 functions to

ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration (Lehto, Mayranpaa et al. 2008). Gene silencing of ORP3 and overexpression of ORP3 in HEK293 cells or primary macrophages demonstrate the function of ORP3 as part of the machinery that controls the actin cytoskeleton, cell polarity and cell adhesion. These functional evidences, together with the abundant expression of ORP3 in polarized cell types, suggest that ORP3 may play an important role in efficient directed membrane trafficking.

**Structure, Tissue distribution and Intracellular localization:** ORP4 belongs to the subfamily I of OSBP/ORP homologues. ORP4 has an ORD, a PH domain and an FFAT motif. ORP4 shares the highest degree of similarity with OSBP and dimerizes with OSBP. Two ORP4 cDNAs were identified: a full-length ORP4 containing a PH domain and an ORD (designated ORP4-L), and a splice variant in which the PH domain and part of the ORD were deleted (designated ORP4-S). ORP4 mRNA and protein expression overlapped partially with OSBP and were restricted to brain, heart, muscle and kidney(Wang, JeBailey

Immunofluorescence localization in stably transfected Chinese hamster ovary cells showed that ORP4-S co-localized with vimentin and caused the intermediate filament network to bundle or aggregate. ORP4-L displayed a diffuse staining pattern that did not overlap with

**Molecular functions related to dyslipidemia:** Cells overexpressing ORP4S had a 40% reduction in the esterification of low-density-lipoprotein-derived cholesterol, demonstrating that ORP4 in an interaction with intermediate filaments inhibits an intracellular cholesterol-

ORP4L bound [3H]25-hydroxycholesterol with high affinity and specificity. However, sterol-binding or a mutation that ablated sterol-binding did not influence the interaction of GST-ORP4 with vimentin (Wyles, Perry et al. 2007). Thus the precise mechanism about what ORP4L senses to regulate intracellular cholesterol-transport pathway still remains

vimentin except when the microtubule network was disrupted with nocodazole.

transport pathway mediated by vimentin (Wang, JeBailey et al. 2002).

**Epidemiological study:** Epidemiological study of ORP4 is not reported yet.

**Epidemiological study:** Epidemiological study of ORP3 is not reported yet.

and the PM, especially thin filopodial cell-surface projections.

regulate Dyslipidemia is yet to be reported.

**2.6 OSBPL4 (ORP4, OSBP2, HLM)** 

et al. 2002).

unidentified.

**2.5 OSBPL3 (ORP3)** 

Mayranpaa et al. 2008).

**Structure, Tissue distribution and Intracellular localization:** ORP5 belongs to the subfamily IV of OSBP/ORP homologues. ORP5 has an ORD, a PH domain and a transmembrane domain. ORP5 localizes to the ER.

**Molecular functions related to dyslipidemia:** Knocking down ORP5 causes cholesterol accumulation in late endosomes and lysosomes, which is reminiscent of the cholesterol trafficking defect in Niemann Pick C (NPC) fibroblasts (Du, Kumar et al. 2011). Cholesterol appears to accumulate in the limiting membranes of endosomal compartments in ORP5 depleted cells, whereas depletion of NPC1 or both ORP5 and NPC1 results in luminal accumulation of cholesterol. Moreover, trans-Golgi resident proteins mislocalize to endosomal compartments upon ORP5 depletion, which depends on a functional NPC1.

Niemann-Pick type C (NPC) disease is most often caused by mutations in the NPC1 gene, whose protein product is believed to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments (Boadu and Francis 2006).

The results of the research by Du et al. establish the first link between NPC1 and a cytoplasmic sterol carrier, and suggest that ORP5 may cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes.

**Epidemiological study:** Epidemiological study of ORP5 is not reported yet.
