**2.11 OSBPL9 (ORP9)**

134 Dyslipidemia - From Prevention to Treatment

GATE-16 is a ubiquitin-like low molecular weight peripheral membrane protein which was initially reported to localize at the Golgi complex and to regulate docking/fusing reactions in intra-Golgi traffic and Golgi assembly from mitotic fragments via interactions with NSF and the Golgi v-SNARE GS28 (Sagiv, Legesse-Miller et al. 2000). GS28 was identified as a SNARE protein, the majority of which is associated with the cis-Golgi, and is implicated in both ER-Golgi and intra-Golgi transport (Subramaniam, Peter et al. 1996). In the presence of NSF, SNAP and ATP, GATE-16 interacts with GS28, apparently maintaining GS28 in a

Zhong et al. revealed that ORP7 knockdown in 293A cells resulted in a 40% increase of GS28 protein while ORP7 overexpression had the opposite effect. Similar to ORP7 overexpression, treatment of cells with 25-hydroxycholesterol (25-OH) resulted in GS28 destabilization, which was potentiated by excess ORP7 and inhibited by ORP7 silencing. Their results suggest that ORP7 negatively regulates GS28 protein stability via sequestration of GATE-16,

**Epidemiological study:** It is reported that SNPs near ORP7 gene show genome-wide

**Structure, Tissue distribution and Intracellular localization:** ORP8 belongs to the subfamily IV of OSBP/ORP homologues. ORP8 has an ORD, a PH domain and a transmembrane domain. ORP8 is expressed at the highest levels in macrophages, liver, spleen, kidney, and brain (Yan, Mayranpaa et al. 2008). ORP8 is localized in the ER via its C-

**Molecular functions related to dyslipidemia:** It is reported that silencing of ORP8 by RNA interference in THP-1 macrophages increased the expression of ABCA1 and concomitantly cholesterol efflux to lipid-free apolipoprotein A-I. Experiments employing an ABCA1 promoter-luciferase reporter confirmed that ORP8 silencing enhances ABCA1 transcription. These data identify ORP8 as a negative regulator of ABCA1 expression and macrophage cholesterol efflux. But the precise mechanism to regulate the expression of ABCA1 has not

Recently, Zhou et al. investigated the action of ORP8 in hepatic cells in vivo and in vitro. They found that adenoviral overexpression of ORP8 in mouse liver induced a decrease of cholesterol, phospholipids, and triglycerides in serum (-34%, -26%, -37%, respectively) and liver tissue (-40%, -12%, -24%), coinciding with reduction of nuclear (n)SREBP-1 and -2 and mRNA levels of their target genes. Consistently, excess ORP8 reduced nSREBPs in HuH7 cells, and ORP8 overexpression or silencing by RNA interference moderately suppressed or induced the expression of SREBP-1 and SREBP-2 target genes, respectively. In accordance, cholesterol biosynthesis was reduced by ORP8 overexpression and enhanced by ORP8

They also performed yeast two-hybrid, bimolecular fluorescence complementation (BiFC), and co-immunoprecipitation analyses, and revealed the nuclear pore component Nup62 as an interaction partner of ORP8. They showed that the impact of overexpressed ORP8 on

These results reveal that ORP8 has the capacity to modulate lipid homeostasis and SREBP

nSREBPs and their target mRNAs was inhibited in cells depleted of Nup62.

activity, probably through an indirect mechanism required Nup62.

transport competent form and protecting it from proteolysis.

and may mediate the effect of 25-OH on GS28 and Golgi function.

**2.10 OSBPL8 (ORP8)** 

been revealed.

terminal transmembrane domain.

silencing in [(3)H]acetate pulse-labeling experiments.

significant association with LDL cholesterol (Teslovich, Musunuru et al. 2010).

**Structure, Tissue distribution and Intracellular localization:** ORP9 belongs to the subfamily V of OSBP/ORP homologues. ORP9 has an ORD, a PH domain and an FFAT motif. VAP binding FFAT motif and PH domains target ORP9 to the ER and a Golgi-COPII compartment, respectively (Wyles and Ridgway 2004).

**Molecular functions related to dyslipidemia:** Ngo et al. demonstrate that ORP9L partitioning between the trans-Golgi/trans-Golgi network (TGN), and the ER is mediated by a phosphatidylinositol 4-phosphate (PI-4P)-specific PH domain and VAP, respectively (Ngo and Ridgway 2009). In vitro, ORP9L mediates PI-4P-dependent cholesterol transport between liposomes, suggesting that its primary function in vivo is sterol transfer between the Golgi and ER. Depletion of ORP9L by RNAi caused Golgi fragmentation, inhibition of vesicular somatitus virus glycoprotein transport from the ER and accumulation of cholesterol in endosomes/lysosomes. These findings indicate that ORP9 maintains the integrity of the early secretory pathway by mediating transport of sterols between the ER and trans-Golgi/TGN.

It is also reported that ORP9, in interaction with ORP11, may act as an intracellular lipid sensor or transporter (Zhou, Li et al. 2010). (see also ORP11.)

**Epidemiological study:** Epidemiological study of ORP9 is not reported yet.
