**2.12 OSBPL10 (ORP10)**

**Structure, Tissue distribution and Intracellular localization:** ORP10 belongs to the subfamily VI of OSBP/ORP homologues. ORP10 has an ORD and a PH domain but does not have an FFAT motif or a transmembrane domain.

ORP10 was shown to associate dynamically with microtubules, being consistent with its involvement in intracellular transport or organelle positioning (Perttila, Merikanto et al. 2009).

Immunofluorescence localization in transiently transfected bovine aorta endothelial cells showed that EGFP-ORP10 co-localized with alpha-tubulin (Fig. 2 c, g) and not with actin (Fig. 2 a, e) or vimentin (Fig. 2 b, f). The microtubules co-localize with EGFP-ORP10 show the aberrant bundled structures. These structures were disrupted by treatment with nocodazol (Fig. 2 d, h).

**Molecular functions related to dyslipidemia:** Silencing of ORP10 increased the incorporation of [(3)H]acetate into cholesterol and both [(3)H]acetate and [(3)H]oleate into triglycerides and enhanced the accumulation of secreted apolipoprotein B100 in growth medium, suggesting that ORP10 suppresses hepatic lipogenesis and very-low-density lipoprotein production.

**Epidemiological study:** We examined the association between polymorphisms in the ORP10 gene and risk factors for the metabolic syndrome in the Tanno and Sobetsu Study in Japan (Koriyama, Nakagami et al. 2010).

Functions of OSBP/ORP Family Proteins and Their Relation to Dyslipidemia 137

plays an important role in that process, the mechanism to control TG and LDL cholesterol

**Structure, Tissue distribution and Intracellular localization:** ORP11 belongs to the subfamily VI of OSBP/ORP homologues. ORP11 has an ORD and a PH domain but does not have an FFAT motif or a transmembrane domain. ORP11 is present at the highest levels in human ovary, testis, kidney, liver, stomach, brain, and adipose tissue. Immunohistochemistry demonstrates abundant ORP11 in the epithelial cells of kidney tubules, testicular tubules, caecum, and skin. ORP11 dimerizes with ORP9 and localizes at

**Molecular functions related to dyslipidemia:** Cells overexpressing ORP11 displayed lamellar lipid bodies associated with vacuolar structures or the Golgi complex, indicating a disturbance of lipid trafficking. Similar multilamellar membranes arise in endo-lysosomal compartments in phospholipidosis occurring, for instance, upon incubation of macrophage with oxidized low-density lipoprotein, or associated with inheritable lysosomal storage disorders, situations in which normal lipid transport is disturbed. These findings indicate that ORP11, in interaction with ORP9, may act as an intracellular lipid sensor or transporter. **Epidemiological study:** it is reported that ORP11 is significantly overexpressed in the visceral adipose tissue of obese men with metabolic syndrome (Bouchard, Faucher et al. 2009). Furthermore, they found SNPs in the ORP11 gene to be associated with several cardiovascular risk factors in obese individuals. IVS12+95 T>C, a newly discovered SNP of the study, was associated with LDL cholesterol levels (OR = 1.63; P < 0.001), hyperglycemia/diabetes (OR = 1.48; P < 0.004) as well as with metabolic syndrome per se (OR = 1.56; P < 0.01). These results suggest that ORP11 is involved in cholesterol and

Since OSBP/ORP family involves functional redundancy as well as overlap tissue expression and intracellular localization, the function of each family member has been mostly left unrevealed. Various studies including the genome-wide association study, however, have succeeded to prove the direct association between the individual members and dyslipidemia. Analyses on the individual members have also made it clear that the members affect the regulation of cholesterol and triglyceride level in interaction with

Nevertheless, the precise molecular mechanism of the process still remains unascertained. The recent findings such as the identification of the small molecule which associates with OSBP are expected to act as a convenient tool to clarify the more detailed functions of

Work in the authors' group is supported by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science and research grants from Takeda Science

levels is yet to be explained. A further analysis is highly expected.

the Golgi-late endosome interface (Zhou, Li et al. 2010).

glucose metabolism in obese individuals.

**3. Conclusion** 

diverse molecules.

OSBP/ORP family in future.

**4. Acknowledgment** 

Foundation.

**2.13 OSBPL11 (ORP11)** 

Fig. 2. Intracellular localization of ORP10.

As a result, we found that the LDL cholesterol of individuals with the rs2290532 (D254N) polymorphism was significantly greater in subjects with the CC+CT genotype than in subjects with the TT genotype (124.3+/-1.3 vs. 111.6+/-4.1 mg per 100 ml, P=0.009) (Fig. 3). Comparison of the genotype frequency in both groups indicated that the genotype associated with low risk (TT) reduced the risk of hyper-LDL cholesterolemia significantly (P=0.003), with an odds ratio of 0.35 (95% confidence interval=0.17-0.76). These findings suggest that the rs2290532 (D254N) polymorphism in OSBPL10 may predispose individuals with this SNP to hyper-LDL cholesterolemia.

Fig. 3. Relation of rs2290532 of ORP10 with serum LDL cholesterol.

Perttila et al. also reported that the analysis of variants in ORP10 gene revealed suggestive linkage of ORP10 single-nucleotide polymorphisms (SNPs) with extreme end high TG (>90th percentile) trait. They carried out an association analysis in a metabolic syndrome subcohort (Genmets) of Health2000 examination survey (N = 2,138), revealing an association of multiple ORP10 SNPs with high serum TG levels (>95th percentile).

The result proves that ORP10 is genetically associated with both TG and LDL cholesterol levels. Though it is estimated that microtubule dependent intracellular transport of vesicles plays an important role in that process, the mechanism to control TG and LDL cholesterol levels is yet to be explained. A further analysis is highly expected.
