**4. Acknowledgment**

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 Foundation.

Functions of OSBP/ORP Family Proteins and Their Relation to Dyslipidemia 139

Lehto, M., M. I. Mayranpaa, et al. (2008). "The R-Ras interaction partner ORP3 regulates cell

Lehto, M., J. Tienari, et al. (2004). "Subfamily III of mammalian oxysterol-binding protein

Levanon, D., C. L. Hsieh, et al. (1990). "cDNA cloning of human oxysterol-binding protein

Levine, T. P. and S. Munro (2002). "Targeting of Golgi-specific pleckstrin homology domains

Ma, L., J. Yang, et al. (2010). "Genome-wide association analysis of total cholesterol and

Mohammadi, A., R. J. Perry, et al. (2001). "Golgi localization and phosphorylation of

Ngo, M. and N. D. Ridgway (2009). "Oxysterol binding protein-related Protein 9 (ORP9) is a

Ngo, M. H., T. R. Colbourne, et al. (2010). "Functional implications of sterol transport by the

North, K. E., L. J. Martin, et al. (2003). "HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q." BMC Genet 4 Suppl 1: S98. Perttila, J., K. Merikanto, et al. (2009). "OSBPL10, a novel candidate gene for high

Radhakrishnan, A., Y. Ikeda, et al. (2007). "Sterol-regulated transport of SREBPs from

Raychaudhuri, S. and W. A. Prinz (2010). "The diverse functions of oxysterol-binding

Ridgway, N. D., K. Badiani, et al. (1998). "Inhibition of phosphorylation of the oxysterol binding protein by brefeldin A." Biochim Biophys Acta 1390(1): 37-51. Ridgway, N. D., P. A. Dawson, et al. (1992). "Translocation of oxysterol binding protein to Golgi apparatus triggered by ligand binding." J Cell Biol 116(2): 307-319. Ridgway, N. D., T. A. Lagace, et al. (1998). "Differential effects of sphingomyelin hydrolysis

Rocha, N., C. Kuijl, et al. (2009). "Cholesterol sensor ORP1L contacts the ER protein VAP to

Sagiv, Y., A. Legesse-Miller, et al. (2000). "GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28." EMBO J 19(7): 1494-1504.

oxysterol-binding protein gene family." Biochem J 429(1): 13-24.

metabolism." J Mol Med (Berl) 87(8): 825-835.

Proc Natl Acad Sci U S A 104(16): 6511-6518.

proteins." Annu Rev Cell Dev Biol 26: 157-177.

localization." J Biol Chem 273(47): 31621-31628.

(OSBP) homologues: the expression and intracellular localization of ORP3, ORP6,

and localization of the gene to human chromosome 11 and mouse chromosome 19."

involves both PtdIns 4-kinase-dependent and -independent components." Curr Biol

high-density lipoprotein cholesterol levels using the Framingham heart study

oxysterol binding protein in Niemann-Pick C and U18666A-treated cells." J Lipid

cholesterol transfer protein that regulates Golgi structure and function." Mol Biol

triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid

endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig."

and cholesterol transport on oxysterol-binding protein phosphorylation and Golgi

control Rab7-RILP-p150 Glued and late endosome positioning." J Cell Biol 185(7):

adhesion." J Cell Sci 121(Pt 5): 695-705.

and ORP7." Cell Tissue Res 315(1): 39-57.

Genomics 7(1): 65-74.

Res 42(7): 1062-1071.

Cell 20(5): 1388-1399.

1209-1225.

data." BMC Med Genet 11: 55.

12(9): 695-704.

### **5. References**


Boadu, E. and G. A. Francis (2006). "The role of vesicular transport in ABCA1-dependent

Bouchard, L., G. Faucher, et al. (2009). "Association of OSBPL11 gene polymorphisms with

Bowden, K. and N. D. Ridgway (2008). "OSBP negatively regulates ABCA1 protein

Burgett, A. W., T. B. Poulsen, et al. (2011). "Natural products reveal cancer cell dependence

Chen, W., G. Chen, et al. (2007). "Enzymatic reduction of oxysterols impairs LXR signaling

Collier, F. M., C. C. Gregorio-King, et al. (2003). "ORP3 splice variants and their expression in human tissues and hematopoietic cells." DNA Cell Biol 22(1): 1-9. Du, X., J. Kumar, et al. (2011). "A role for oxysterol-binding protein-related protein 5 in

Fairn, G. D. and C. R. McMaster (2008). "Emerging roles of the oxysterol-binding protein family in metabolism, transport, and signaling." Cell Mol Life Sci 65(2): 228-236. Hynynen, R., M. Suchanek, et al. (2009). "OSBP-related protein 2 is a sterol receptor on lipid

Jansen, M., Y. Ohsaki, et al. (2011). "Role of ORPs in sterol transport from plasma membrane to ER and lipid droplets in mammalian cells." Traffic 12(2): 218-231. Johansson, M., V. Bocher, et al. (2003). "The two variants of oxysterol binding protein-related

localization, and are functionally distinct." Mol Biol Cell 14(3): 903-915. Johansson, M., M. Lehto, et al. (2005). "The oxysterol-binding protein homologue ORP1L

Johansson, M., N. Rocha, et al. (2007). "Activation of endosomal dynein motors by stepwise

Kobuna, H., T. Inoue, et al. (2010). "Multivesicular body formation requires OSBP-related

Koriyama, H., H. Nakagami, et al. (2010). "Variation in OSBPL10 is associated with

Lagace, T. A., D. M. Byers, et al. (1997). "Altered regulation of cholesterol and cholesteryl

Lagace, T. A., D. M. Byers, et al. (1999). "Chinese hamster ovary cells overexpressing the

Laitinen, S., M. Lehto, et al. (2002). "ORP2, a homolog of oxysterol binding protein, regulates

response to 25-hydroxycholesterol." J Lipid Res 40(1): 109-116.

cellular cholesterol metabolism." J Lipid Res 43(2): 245-255.

droplets that regulates the metabolism of neutral lipids." J Lipid Res 50(7): 1305-

protein-1 display different tissue expression patterns, have different intracellular

interacts with Rab7 and alters functional properties of late endocytic

assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin." J Cell

ester synthesis in Chinese-hamster ovary cells overexpressing the oxysterolbinding protein is dependent on the pleckstrin homology domain." Biochem J 326 (

oxysterol binding protein (OSBP) display enhanced synthesis of sphingomyelin in

in cultured cells and the livers of mice." Cell Metab 5(1): 73-79.

endosomal cholesterol trafficking." J Cell Biol 192(1): 121-135.

stability." J Biol Chem 283(26): 18210-18217.

on oxysterol-binding proteins." Nat Chem Biol.

compartments." Mol Biol Cell 16(12): 5480-5492.

proteins and cholesterol." PLoS Genet 6(8).

dyslipidemia." Hypertens Res 33(5): 511-514.

lipid efflux and its connection with NPC pathways." J Mol Med (Berl) 84(4): 266-

cardiovascular disease risk factors in obesity." Obesity (Silver Spring) 17(7): 1466-

**5. References** 

275.

1472.

1315.

Biol 176(4): 459-471.

Pt 1): 205-213.


**8** 

*Slovakia* 

**Adipose Tissue and Skeletal Muscle Plasticity** 

**in Obesity and Metabolic Disease** 

*1Institute of Experimental Endocrinology Slovak Academy of Sciences,* 

*2Institute of Pathological Physiology, Faculty of Medicine Comenius University,* 

Obesity and lack of physical activity are two major factors contributing considerably to the pathogenesis of many chronic diseases so prevalent in contemporary human population. Adipose tissue and skeletal muscle are therefore the primary organs one would immediately suggest to target in an attempt to battle metabolic disease progression. Fine tuning of the physiological processes within the two organs have a large potential to modulate (i) energy balance, (ii) lipid storage-utilization efficiency as well as (iii) central and peripheral actions in the brain, gastrointestinal system or liver which are integrated by the endocrine activity

Despite the fact that the primary role of adipose tissue is an effective lipid storage and timely regulation of its release and that these processes could, in a simplified adipocentric view, be the primary determinants of the dyslipidemia and metabolic disease progression, adipose tissue has a broad range of other regulatory functions exerted *via* its autocrine, paracrine and endocrine actions. Adipose tissue secretory products, "adipokines", could modulate food intake, energy expenditure, or tissue oxidative capacity (Trayhurn et al. 1998; Ukropec et al. 2001; Ahima & Lazar 2008; Henry & Clarke 2008; Friedman 2011). In addition, adipose tissue dynamically changes its structure (*tissue remodeling, lipid composition*), function (*lipid storage & lipolysis*) as well as endocrine action in response to different physiological (*fasting / refeeding, exercise, microgravity*) and pathophysiological (*obesity, prediabetes, diabetes, cachexia, lipodystrophy, growth hormone deficiency*) conditions (Ukropec et al. 2008; Itoh et al. 2011; Pietilainen et al. 2011). It is important to understand that adipose tissue is a mixture of very different cell-types. Apart from approximately 50% of mature lipid-laden adipocytes it contains various stromal cells including preadipocytes, endothelial cells, fibroblasts, pluripotent stem cells and immune cells which substantially influence its function (Bjorntorp 1974; Sethi & Vidal-Puig 2007; Divoux & Clement 2011). Extreme enlargement of the fat cell size, such as we have recently observed in individuals with growth hormone deficiency, is perhaps the best early marker of the obesity related metabolic disease development (Ukropec et al. 2008a) (Fig. 1.). Adipose tissue with enlarged adipocytes, expressing markers of the local tissue microhypoxia but not responding to it

**1. Introduction** 

of the two energy balance maintaining tissues.

**2. Adipose tissue in metabolic health and disease** 

Jozef Ukropec1 and Barbara Ukropcova1,2

