**2. Overview of functions of OSBP/ORP family proteins and their relation to dyslipidemia**

It has become widely known that each member of OSBP/ORP family respectively affects diverse processes considered to have an association with dyslipidemia, such as intracellular trafficking of cholesterol or neutral lipid. The first presented is a brief overview of the members as a whole before the individual explanation of each member.

Functions of OSBP/ORP Family Proteins and Their Relation to Dyslipidemia 129

proteins in the ER. The human ORP1L have at their N-terminus ankyrin repeats, which interacts with the active GTP-bound form of Rab7 on late endosomes, and thus mediates

Human OSBP/ORP family members are arranged into subfamilies I-VI. The color codes are: red, OSBP-related domain (ORD); yellow, OSBP-fingerprint (OF) motif; green, pleckstrin homology (PH) domain; Blue, ankirin repeats; black, VAP targeting motif (FFAT motif); Orange, transmembrane domain. L and S in the protein names indicate long and short

**Structure, Tissue distribution and Intracellular localization:** OSBP belongs to the subfamily I of OSBP/ORP homologues. OSBP has an ORD, a PH domain and an FFAT motif. OSBP shares the highest degree of similarity with ORP4 and dimerizes with ORP4. In the transfected cells, some of the OSBP was distributed diffusely in the cytoplasm, and some was bound to small vesicles near the nucleus. Upon addition of 25-hydroxycholesterol, most of the OSBP became concentrated in the Golgi apparatus (Ridgway, Dawson et al. 1992). **Molecular functions related to dyslipidemia:** OSBP is the founding member of the OSBP/ORP family. Human OSBP was cloned in 1990 (Levanon, Hsieh et al. 1990) and was studied intensively (Ridgway, Dawson et al. 1992; Lagace, Byers et al. 1997; Ridgway, Badiani et al. 1998; Ridgway, Lagace et al. 1998; Storey, Byers et al. 1998; Lagace, Byers et al.

Yan et al. reported that adenovirus-mediated hepatic overexpression of OSBP induced a marked increase of VLDL TG. Also, the liver tissue TG were elevated in the AdOSBPinjected mice, and their TG secretion rate was increased by 70%. The messenger RNAs for enzymes of fatty acid synthesis and their transcriptional regulator, SREBP-1c, as well as the

targeting of the protein to late endosomes.

Fig. 1. Domain organization of the humam OSBP/ORP family.

1999; Mohammadi, Perry et al. 2001; Levine and Munro 2002).

variants, respectively.

**2.2 OSBP** 

OSBP negatively regulates ATP-binding cassette transporter A1 (ABCA1) protein stability (Bowden and Ridgway 2008). OSBP induces upregulation of SREBP-1c and enhances hepatic lipogenesis (Yan, Lehto et al. 2007).

ORP1L forms a RILP-Rab7-ORP1L complex (Johansson, Rocha et al. 2007) and is involved in both protein and lipid transport functions of the late endocytic compartments (Vihervaara, Uronen et al. 2011).

ORP1S and ORP2 enhance plasma membrane (PM)-to-lipid droplet (LD) sterol transport (Jansen, Ohsaki et al. 2011). ORP2 presents on LD and has a functional role in the regulation of neutral lipid metabolism, possibly as a factor that integrates the cellular metabolism of triglycerides (TG) with that of cholesterol (Hynynen, Suchanek et al. 2009).

ORP3 may play an important role in efficient directed membrane trafficking (Lehto, Mayranpaa et al. 2008). But the direct evidence that ORP3 functions to regulate dyslipidemia is yet to be reported.

ORP4 in an interaction with intermediate filaments inhibits an intracellular cholesteroltransport pathway mediated by vimentin (Wang, JeBailey et al. 2002).

ORP5 may cooperate with Niemann-Pick C1 (NPC1) to mediate the exit of cholesterol from endosomes/lysosomes (Du, Kumar et al. 2011).

ORP6 is identified as one of the candidate genes that are possibly involved in the regulation of high-density lipoprotein (HDL) cholesterol levels (North, Martin et al. 2003).

SNPs near ORP7 gene show a genome-wide significant association with low-density lipoprotein (LDL) cholesterol (Teslovich, Musunuru et al. 2010).

ORP8 negatively regulates ABCA1 expression and macrophage cholesterol efflux (Yan, Mayranpaa et al. 2008). ORP8 has the capacity to modulate lipid homeostasis and SREBP activity, probably through an indirect mechanism required Nup62 (Zhou, Li et al. 2011). The OSBPL8-ZDHHC17 region (chr12) is detected for HDL cholesterol identified by one new SNP with genome-wide significance (Ma, Yang et al. 2010).

ORP9 and ORP11 are dimerized and may act as an intracellular lipid sensor or transporter (Zhou, Li et al. 2010).

ORP10 suppresses hepatic lipogenesis and very-low-density lipoprotein production (Perttila, Merikanto et al. 2009). ORP10 is genetically associated with both TG (Perttila, Merikanto et al. 2009) and LDL cholesterol level (Koriyama, Nakagami et al. 2010).

SNPs in the ORP11 gene is associated with LDL cholesterol levels, hyperglycemia /diabetes as well as with metabolic syndrome per se (Bouchard, Faucher et al. 2009).
