**Author details**

Jasmina Dimitrova-Shumkovska\*

*Institute of Biology, Department of Experimental Biochemistry and Physiology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University - Skopje, Republic of Macedonia* 

Leo Veenman, Inbar Roim and Moshe Gavish

*Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Department of Molecular Pharmacology, Haifa, Israel* 

#### **4. References**


<sup>\*</sup> Jasmina Dimitrova-Shumkovska and Leo Veenman contributed equally to this book chapter.

protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis. *Atherosclerosis.* 210(2):388-91.


108 Lipid Metabolism

ONOO-

**Author details** 

**4. References** 

Jasmina Dimitrova-Shumkovska\*

*Eur J Pharmacol.* 110:41-6.

*Neuroscience.* 116:437-45.

*Neurocytol.* 26:77-82.

*Arch Int Pharmacodyn Ther.* 266:38-49.

*Res.* 45:403-9.

 \*

molecule; VSMCs, vascular smooth muscle cells.

Leo Veenman, Inbar Roim and Moshe Gavish

*Technology, Department of Molecular Pharmacology, Haifa, Israel* 

equilibrium dissociation constant; *K*m, equilibrium constant related to Michaelis-Menten kinetics (similarly, *K*d, *K*a, *K*eq, *K*s); LDL, low density lipoproteins; mPTP, mitochondrial permeability transition pore; MCP-1, monocyte chemoatractant proteins-1; NADP, nicotinamide adenine dinucleotide phosphate; NADH, reduced nicotinamide adenine dinucleotide; PBR, peripheral-type benzodiazepine receptor; PC protein carbonyls; PK 11195, 1-(2- chlorophenyl)-N-methyl-N-(1-methyl-prop1)-3 isoquinolinecarboxamide;

superoxide dismutase activity; TBARs, thiobarbituric acid reactive substances; TNF, tumor necrosis factor; TSPO, 18 kDa translocator protein; VCAM-1, vascular cell adhesion

*Institute of Biology, Department of Experimental Biochemistry and Physiology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University - Skopje, Republic of Macedonia* 

Anholt, R.R., De Souza, E.B., Kuhar, M.J., & Snyder, S.H. (1985). Depletion of peripheraltype benzodiazepine receptors after hypophysectomy in rat adrenal gland and testis.

Aono, M., Bennett, E.R., Kim, K.S., Lynch, J.R., Myers, J., Pearlstein, R.D., Warner, D.S., & Laskowitz, D.T. (2003). Protective effect of apolipoprotein E-mimetic peptides on Nmethyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures.

Banati, R.B., Myers, R., & Kreutzberg, G.W. (1997). PK ('peripheral benzodiazepine')- binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H] PK11195 binding to activated microglia. *J* 

Beffert, U., Stolt, P.C., & Herz, J. (2004). Functions of lipoprotein receptors in neurons*. J Lipid* 

Benavides, J., Malgouris, C., Imbault, F., Begassat, F., Uzan, A., Renault, C., Dubroeucq, M.C., Gueremy, C., & Le Fur, G. (1983). "Peripheral type" benzodiazepine binding sites in rat adrenals: binding studies with [3H] PK 11195 and autoradiographic localization.

Bird, J.L., Izquierdo-Garcia, D., Davies, J.R., Rudd, J.H., Probst, K.C., Figg, N, Clark, J.C., Weissberg, P.L., Davenport, A.P., & Warburton, E.A. (2010). Evaluation of translocator

Jasmina Dimitrova-Shumkovska and Leo Veenman contributed equally to this book chapter.

*Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of* 

, peroxinitrite ; Ro5-4864, (4'- chlorodiazepam); ROS , reactive oxygen species; SOD,


Dansky, H., Sherri, A., Charlton, S.A., Sikes, J., Heath, S., Simantov, R., Levin, L., Shu, P., Moore,K., Breslow, J., Smith, J.(1999). Genetic background determines the extent of atherosclerosis in ApoE deficient mice. *Arterioscler.Thromb.Vasc.Biol.* 19:1960-1968.

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E 111

collateral formation and those designed to inhibit atherogenesis. *Circulation.* 109(23):

Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, & Diaz, G. (2007). Intracellular cholesterol changes induced by translocator protein (18 kDa)

Fares, F., Weizman, A., Pick, C.G. & Gavish, M. (1990). Effect of prenatal and neonatal chronic exposure to phenobarbital on central and peripheral benzodiazepine receptors.

Finsen, B. (2006). Up-regulation of PK11195 binding in areas of axonal degeneration coincides with early microglial activation in mouse brain. *Eur J Neurosci.* 24:991-1000. Friedewald WT, Levy RI, & Fredrickson DS. (1972). Estimation of the concentration of lowdensity lipoprotein cholesterol in plasma, without use of the preparative centrifuge.

Gaemperli, O., Shalhoub, J., Owen, D. R.J., Lamare, F., Johansson, S., Fouladi, N., Davies, A.H., Rimoldi, O.E., Camici, P.G. (2011). Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed

Gaemperli, O., Shalhoub,J., Owen, D.R.J, Lamare,D., Johansson, S., Fouladi, N., Davies, A., Ornella, E., Rimoldi, O.E.,& Camici, P., (2012). Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed

Gavish, M. & Fares, F. (1985).Solubilization of peripheral benzodiazepine-binding sites from

Gavish, M., Bar-Ami, S., & Weizman, R. (1992). The endocrine system and mitochondrial

Gavish, M. & Weizman, R. (1997). Role of peripheral-type benzodiazepine receptors in

Gavish, M., Bachman, I., Shoukrun, R., Katz, Y., Veenman, L., Weisinger, G. & Weizman, A. (1999). Enigma of the peripheral benzodiazepine receptor. *Pharmacol. Review*. 51, 630-

Gunten, A.V., Ebbing, K., Imhof, A., Giannakopoulos, P., Kovari, E. (2010). Brain aging in

Han, S.H., Einstein, G., Weisgraber, K.H., Strittmatter, W.J., Saunders, A.M., Pericak-Vance, M., Roses, A.D., & Schmechel, D.E. (1994). Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. *J* 

Harris, F.M., Tesseur, I., Brecht, W.J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R.W., & Huang, Y. (2004). Astroglial regulation of apolipoprotein E expression

in neuronal cells. Implications for Alzheimer's disease*. J Biol Chem*. 279:3862-8. Hashimoto, K., Inoue, O., Suzuki, K., Yamasaki, T., & Kojima, M. (1989). Synthesis and evaluation of 11C-PK 11195 for in vivo study of peripheral-type benzodiazepine

receptors using positron emission tomography. *Ann Nucl Med*. 3:63-71.

TSPO/PBR ligands. *Neuropharmacology.* 53:318-29.

tomography. *Eur Heart J.* 33(15):1902-1910.

tomography. *Eur Heart J.* 33(15): 1902-1910.

benzodiazepine receptors. *Mol Cell Endocrinol.* 88, 1-13.

steroidogenesis. *Clin Neuropharmacol.* 20:473-81.

the Oldest-Old. *Curr. Gerontol Geriatr. Res.* 358531.

rat kidney. *J Neurosci*. 5:2889-93.

*Neuropathol Exp Neurol*. 53:535-44.

646.

2826-31.

*Brain Res.* 506(1): 115-9.

*Clin Chem*; 18:499—500.


collateral formation and those designed to inhibit atherogenesis. *Circulation.* 109(23): 2826-31.

Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, & Diaz, G. (2007). Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands. *Neuropharmacology.* 53:318-29.

110 Lipid Metabolism

Dansky, H., Sherri, A., Charlton, S.A., Sikes, J., Heath, S., Simantov, R., Levin, L., Shu, P., Moore,K., Breslow, J., Smith, J.(1999). Genetic background determines the extent of atherosclerosis in ApoE deficient mice. *Arterioscler.Thromb.Vasc.Biol.* 19:1960-1968. Davignon, J., Gregg, R.E., & Sing, C.F. (1988). Apolipoprotein E polymorphism and

Davignon, J., Cohn, J.S., Mabile, L., & Bernier, L. (1999). Apolipoprotein E and

Dimitrova-Shumkovska, J., Veenman, L., Ristoski, T., Leschiner, S., & Gavish, M. (2010a). Chronic High Fat, High Cholesterol Supplementation Decreases 18 kDa Translocator Protein Binding Capacity in Association with Increased Oxidative Stress in Rat Liver

Dimitrova-Shumkovska, J., Veenman, L., Ristoski, T., Leschiner, S., & Gavish, M. (2010b). Dimethylbenz [alpha] anthracene induces oxidative stress and reduces the binding capacity of the mitochondrial 18-kDa translocator protein in rat aorta. *Drug Chem.* 

Dimitrova-Shumkovska, J., Veenman, L., Ristoski, T., Leschiner, S., & Gavish, M. (2010c). Decreases in Binding Capacity of the Mitochondrial 18 kDa Translocator Protein Accompany Oxidative Stress and Pathological Signs in Rat Liver after DMBA Exposure*.* 

Dimitrova-Shumkovska, J., Veenman, & Gavish, M. (2012). The 18kDa Translocator Protein as a Potential Participant in Atherosclerosis, in the book : ,,Atherogenesis", edited by

Do Carmo, S., Seguin, D., Milne, R. & Rassart, E. (2002). Modulation of apolipoprotein D and apolipoprotein E mRNA expression by growth arrest and identification of key elements

Dumont , F., De Vos, F., Versijpt, J., Jansen, H.M., Korf, J., Dierckx, R.A., & Slegers, G. (1999). In vivo evaluation in mice and metabolism in blood of human volunteers of [123I]iodo-PK11195: a possible single-photon emission tomography tracer for visualization of

Dupont-Wallois, L., Soulié, C., Sergeant, N., Wavrant-de Wrieze, N., Chartier-Harlin, M.C., Delacourte, A.,& Caillet-Boudin, M.L. (1997). ApoE synthesis in human neuroblastoma

Elliot, A.J., Maier, M.A., Moller, A.C., Friedman, R. & Meinhardt, J. (2007). Color and psychological functioning: the effect of red on performance attainment. *J Exp Psychol* 

Elliott, D.A., Kim, W.S., Jans, D.A., & Garner, B. (2007). Apoptosis induces neuronal apolipoprotein-E synthesis and localization in apoptotic bodies. *Neurosci Lett.* 416:206-

Elshourbagy N.A., Liao W.S., Mahley R.W., & Taylor J.M. (1985). Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other

Epstein, S.E., Stabile, E., Kinnaird, T., Lee, C.W., Clavijo, L. & Burnett, M.S. (2004). Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance

peripheral tissues of rats and marmosets. *Proc Natl Acad Sci* U S A. 82:203-7.

atherosclerosis:insight from animal to human studies. 286:115-143.

atherosclerosis. *Arteriosclerosis.* 8:1-21. 1988.

and Aorta. *Food and Chem. Toxicol*. 48, 910-921.

Parthasarathy, S., INTECH, ISBN 978-953-307-992-9

in the promoter. *J Biol Chem*. 277: 5514-23

inflammation. *Eur J Nucl Med.* 26:194-200.

cells. *Neurobiol Dis.* 4:356-64.

*Gen.* 136(1): 154-68.

10.

*Toxicol*. 33, 337-47.

*Toxicol Pathol*., 38:957-68.


Hasty, A.H., Linton, M.F., Brandt, S.J., Babaev, V.R., Gleaves, L.A., & Fazio, S. (1999). Retroviral gene therapy in ApoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation. *Circulation.* 99:2571-6.

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E 113

Krueger, K.E & Papadopoulos, V. (1990). Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in

Krul, E.S., Tikkanen, M.J., & Schonfeld, G. (1988). Heterogeneity of apolipoprotein E epitope expression on human lipoproteins:importance for apolipoprotein E function*. J Lipid Res*.

Kunitomo, M., Yamaguchi, Y., Kagota, S., Yoshikawa, N., Nakamura, K., & Shinozuka, K. (2009). Biochemical Evidence of Atherosclerosis Progression Mediated by Increased Oxidative Stress in Apolipoprotein E-Deficient Spontaneously Hyperlipidemic Mice

Lacapère, J.J. & Papadopoulos, V. (2003). Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis.

Laskowitz, D. T. (2003). APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response*. J Biol Chem.* 278:48529-33. Law, G.L., McGuinness, M.P., Linder, C.C., & Griswold, M.D. (1997). Expression of apolipoprotein E mRNA in the epithelium and interstitium of the testis and the

Lenfant, M., Zavala, F., Haumont, J., & Potier, P. (1985). [Presence of a peripheral type benzodiazepine binding site on the macrophage; its possible role in

Levine, R. L., Garland, D., Oliver, C.N., Amici, A., Climent, I., Lenz, A.G., Ahn, B.W., Shaltiel, S., & Stadman, E.R. (1990). Determination of carbonyl content in oxidatively

Libby, P., Ridker, P.M. & Hansson, G.K. (2011). Progress and challenges in translating the

Linton, MF. & Fazio, S. (1999). Macrophages, lipoprotein metabolism, and atherosclerosis: insights from murine bone marrow transplantation studies. *Curr Opin Lipidol*. 10:97-105. Liu S.X., Hou, F.F., Guo, Z. J., Nagai, R., Zhang, W.R., Liu, Z.Q., Zhou, Z.M., Di Xie, Wang, G.B., & Zhang, X. (2006). Advanced Oxidation Protein Products Accelerate Atherosclerosis Through Promoting Oxidative Stress and Inflammation. *Arterioscler* 

Lynch, J.R., Tang, W, Wang, H., Vitek, M.P., Bennett ,E.R., Sullivan, P.M., Warner, D.S., Mahley, R.W. (1988). Apolipoprotein E: cholesterol transport protein with expanding role in

Mahley, R.W., & Huang, Y. (1999a). Apolipoprotein E: from atherosclerosis to Alzheimer's

Mahley, R.W. & Ji, Z.S. (1999b). Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. *J Lipid Res*. 40:1-16. Mahley, R.W. & Rall, S.C. Jr. (2000). Apolipoprotein E: far more than a lipid transport

Mahley, R.W., Huang, Y., & Weisgraber, K.H. (2006).Putting cholesterol in its place: apoE

Exposed to Chronic Cigarette Smoke. *J Pharmacol. Sci*. 110, 354-361

adrenocortical cells. *J Biol Chem.* 265:15015-22.

29:1309-25.

*Steroids.* 68:569-85.

epididymis. *J Androl.* 18:32-42.

*Thromb Vasc Biol*. 26, 1156-1162.

cell biology. *Science.* 240(4582): 622-30.

disease and beyond. *Curr Opin Lipidol*. 10:207-17.

protein. *Annu Rev Genomics Hum Genet*. 1:507-37.

and reverse cholesterol transport*. J Clin Invest*. 116:1226-9.

immunomodulation] *C R Acad Sci* III. 300:309-14.

modified proteins. *Methods in Enzymol.* 186, 464-478.

biology of atherosclerosis. Review. *Nature* 473:317-325

Heumann, R., Lindholm, D., Bandtlow, C., Meyer, M., Radeke, M.J., Misko, T.P., Shooter, E.,


Krueger, K.E & Papadopoulos, V. (1990). Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. *J Biol Chem.* 265:15015-22.

112 Lipid Metabolism

93(3): 262-9.

1430.

9.

161:1-151.

*Res.* 105, 849-854.

*Circ Res*. 93, 262-269.

receptors, and enzymes*. J Neurosci.* 5:2240-53.

adenovirus vectors. *J Clin Invest.* 96:1612-20.

responses to medical treatment. *Am J Med*. 122:S3-S14.

Hasty, A.H., Linton, M.F., Brandt, S.J., Babaev, V.R., Gleaves, L.A., & Fazio, S. (1999). Retroviral gene therapy in ApoE-deficient mice: ApoE expression in the artery wall

Heumann, R., Lindholm, D., Bandtlow, C., Meyer, M., Radeke, M.J., Misko, T.P., Shooter, E., Hoen, P.A., Van der Lans, C.A., Van Eck, M., Bijsterbosch, M.K., Van Berkel, T.J. & Twisk, J. (2003). Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes. *Circ Res.* 

Hoen, P.A.C., Van der Lans, C.A.C., Van Eck, M., Bijsterbosch, M.K., Van Berkel & T.J.C., Twisk, J. (2003). Aorta of ApoE – deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes.

Hollingsworth, E.B., McNeal, E.T., Burton, J.L., Williams, R.J., Daly, J.W., & Creveling, C.R. (1985). Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3':5'-monophosphate-generating systems,

Insull, W.Jr. (2009). The pathology of atherosclerosis: Plaque development and plaque

Johnson, J., Carson,K., Williams, H., Karanam, S., Newby, A., & Angelini, G. (2005). Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse:model characterization and effects of pravastatin treatment. *Circulation*.111:1422-

Kashyap, V.S., Santamarina-Fojo, S., Brown, D.R., Parrott, C.L., Applebaum-Bowden, D., Meyn, S., Talley, G., Paigen, B., Maeda, N., & Brewer, H.B. Jr. (1995). Apolipoprotein E deficiency in mice: gene replacement and prevention of atherosclerosis using

Kato R, Mori C, Kitazato K, Arata S, Obama T, Mori M, Takahashi K, Aiuchi T, & Takano T. (2009). Transient increase in plasma oxidized LDL during the progression of atherosclerosis in apolipoprotein E knockout mice. *Arterioscler Thromb Vasc Biol.* 29: 33–

Klegeris, A., McGeer, E.G., & McGeer, P.L. (2000). Inhibitory action of 1-(2-chlorophenyl)-Nmethyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK 11195) on some

Kmieć Z. (2001). Cooperation of liver cells in health and disease. *Adv Anat Embryol Cell Biol*.

Knight-Lozano, C.A., Young, C.G., Burow, D.L., Hu, Z.Y., Uyeminami, D., Pinkerton, K.E., Ischiropulos, H., & Ballinger, S.W. (2002). Cigarette smoke exposure and hypercholesterolemia increase mitochondrial damage in cardiovascular tissues. *Circ* 

Ko, K.W.S., Paul, A., Ma, K., Li, L., Chan, L. (2005) Endothelial lipase modulates plasma lipoprotein profiles but has no effect on the development od atherosclerosis in

mononuclear phagocyte functions. *Biochem Pharmacol*. 59:1305-14.

ApoE*−/−* and LDLR*−/<sup>−</sup>* mice. *J Lipid Res.* 46:2586-2594.

reduces early foam cell lesion formation. *Circulation.* 99:2571-6.


Marchetti, P., Trincavelli, L., Giannarelli, R., Giusti, L., Coppelli, A., Martini, C., & Marshall, J.S. (2004). Mast-cell responses to pathogens. *Nat Rev Immunol*. 4:787-99.

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E 115

Rosenfeld, M.E., Polinsky, P., Virmani, R., Kauser, K., Rubanyi,G., Schwartz, S.M. (2000). Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse.

Ross, J.S., Stagliano, N.E., Donovan, M.J., Breitbart, R.E., & Ginsburg, G.S. (2001). Atherosclerosis And Cancer: Common Molecular Pathways Of Disease Development And Progression. *Ann NY Acad Sci*. 947, 271–292Ruff, M.R., Wahl S.M., Mergenhagen, S., & Pert, C.B. (1985). Opiate receptor-mediated chemotaxis of human monocytes.

Ross, R & Glomset, J.A. (1973). Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of

Ryu, J.K., Choi, H.B., & McLarnon, J.G. (2005). Peripheral benzodiazepine receptor ligand PK11195 reduces microglial activation and neuronal death in quinolinic acid-injected

Schafer, F.Q., Buettner, G.R. (2001) . Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. *Free Radic Biol Med.* 30:1191-

Sehayek, E., Shefer, S., Nguyen, L.B., Ono, J.G., Merkel, M., & Breslow, J.L. (2000). Apolipoprotein E regulates dietary cholesterol absorption and biliary cholesterol excretion: studies in C57BL/6 apolipoprotein E knockout mice. *Proc Natl Acad Sci* U S A.

Seo, T., Qi, K., Chang, C., Liu, Y., Worgall, T.S., Ramakrishan, R., & Deckelbaum, R.J. (2005). Saturated fat-rich diet enhances selective uptake of LDL cholesteryl esters in the arterial

Shargorodsky, L., Veenman, L., Caballero, B., Pe'er, Y., Leschiner, S., Bode, J., Gavish, M. (2012). The nitric oxide donor sodium nitroprusside requires the 18 kDa Translocator

Sheng, H., Laskowitz, D.T., Bennett, E., Schmechel, D.E., Bart, R.D., Saunders, A.M., Pearlstein, R.D., Roses, A.D., & Warner, D.S. (1998). Apolipoprotein E isoform-specific differences in outcome from focal ischemia in transgenic mice. *J Cereb Blood Flow Metab*.

Singh, V., Tiwari, R.L., Dikshit, M., & Barthwal, M.K. (2009). Models to Study

Stannard, A.K., Riddell, D.R., Sacre, S.M., Tagalakis, A.D., Langer, C., von Eckardstein, A., & Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., & Witztum, J.L. (1989). Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. *N* 

Steinberg, D. (2002). Atherogenesis in perspective: hypercholesterolemia and inflammation

Stephenson, D.T., Schober, D.A., Smalstig, E.B., Mincy, R.E., Gehlert, D.R., & Clemens, J.A. (1995). Peripheral benzodiazepine receptors are colocalized with activated microglia

following transient global forebrain ischemia in the rat. *J Neurosci*. 15:5263-74.

Atherosclerosis: A Mechanistic Insight. *Curr Vasc Pharmacol.* 7, 75-109.

Ross, R., (1999). Atherosclerosis an Inflammatory Disease. *N Engl J Med*. 340, 115-26.

*Arterioscler. Thromb. Vasc. Biol*.20:2587-2592.

atherosclerosis. *Science* 180: 1332-1339.

rat striatum. *Neurobiol Dis.* 20:550-61.

wall. *J Clin Invest.* 115, 2214-2222.

Protein to induce cell death. *Apoptosis.* 17:647-65.

as partners in crime*. Nat Med* 8, 1211–1217.

*Neuropeptides*. 5:363-6.

212.

97:3433-7.

18:361-6.

*Engl J Med.* 320:915-924


Rosenfeld, M.E., Polinsky, P., Virmani, R., Kauser, K., Rubanyi,G., Schwartz, S.M. (2000). Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. *Arterioscler. Thromb. Vasc. Biol*.20:2587-2592.

114 Lipid Metabolism

Marchetti, P., Trincavelli, L., Giannarelli, R., Giusti, L., Coppelli, A., Martini, C., & Marshall,

Mazurika, C., Veenman, L., Weizman, R., Bidder, M., Leschiner ,S., Golani, I., Spanier, I., Weisinger, G., & Gavish, M. (2009). Estradiol modulates uterine 18 kDa translocator protein gene expression in uterus and kidney of rats. *Mol Cell Endocrinol.* 307, 43-49. McAdoo, J.D., Warner, D.S., Goldberg, R.N., Vitek, M.P., Pearlstein, R., & Laskowitz, D.T. (2005). Intrathecal administration of a novel apoE-derived therapeutic peptide improves

outcome following perinatal hypoxic-ischemic injury. *Neurosci Lett*. 381:305-8. Milner, P., Bodin, P., Guiducci, S., Del Rosso, A., Kahaleh, M.B., Matucci-Cerinic, M., & Burnstock, G. (2004). Regulation of substance P mRNA expression in human dermal

Morgan, J., Oseroff, A.R., & Cheney, R.T. (2004). Expression of the peripheral benzodiazepine receptor is decreased in skin cancers in comparison with normal skin.

Nakashima, Y., Raines, E.W., Plump, A.S., Breslow, J.L., & Ross, R. (1998). Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-

Navalesi, R. & Lucacchini, A. (1996). Characterization of peripheral benzodiazepine receptors in purified large mammal pancreatic islets. *Biochem Pharmacol*. 51:1437-42. Noeman, S.A., Hamooda, H.E., & Baalash, A.A. (2011). Biochemical study of oxidative stress markers in the liver, kidney and heart of high fat diet induced obesity in rats. *Diabetol* 

Onyimba, J.A., Coronado, M.J., Garton, A.E., Kim, J.B., Bucek, A., Bedja, D., Gabrielson, K.L., Guilarte, T.R., & Fairweather, D. (2011). The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice. *Biol* 

Papadopoulos, V., Baraldi, M., Guilarte, T.R., Knudsen, T.B., Lacapère, J.J., Lindemann, P., Norenberg, M.D., Nutt, D., Weizman, A., Zhang, M.R., & Gavish, M. (2006). Translocator protein (18kDa). New nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. *Trends* 

Papadopoulos, V., Berkovich, A., Krueger, K.E., Costa, E., & Guidotti, A. (1991). Diazepam binding inhibitor and its processing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors.

Pedersen, M.D., Minuzzi, L., Wirenfeldt ,M., Meldgaard, M., Slidsborg, C., Cumming, P., Potter, H., Wisniewski, T. (2012). Apolipoprotein E: Essential catalyst of the Alzheimer

Quinn, C.M., Kågedal, K., Terman, A., Stroikin U., Brunk, U.T., Jessup, W., & Garner, B. (2004). Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-

microvascular endothelial cells. *Clin Exp Rheumatol*. 22:S24-7.

deficient mouse. *Arterioscler Thromb Vasc Biol*. 18:842-51.

*Br J Dermatol*. 151, 846-56.

*Metab Syndr*. 3(1), 17.

*Sex Differ.* 21; 2:2.

*Pharmacol Sci.* 27, 402-9.

*Endocrinology*. 129:1481-8.

amyloid cascade. *Int J Alzheimers Dis.* 489428.

induced growth arrest and mitosis. *Biochem J*. 378:753-61. 2004.

J.S. (2004). Mast-cell responses to pathogens. *Nat Rev Immunol*. 4:787-99.


Stocker, R & Keaney, JF Jr. (2004). Role of oxidative modifications in atherosclerosis. *Physiol Rev.* 84,1381–478.

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E 117

gene expression of glutamate receptors, transporters, and metabolism, and on cell

Veiga, S., Azcoitia, I., Garcia-Segura, L.M. (2005). Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from

Vowinckel, E., Reutens, D., Becher, B., Verge, G., Evans, A., Owens, T., Antel, J.P.(1997). PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. *J* 

Waterfield, J.D., McGeer, E.G., McGeer, P.L. (1999). The peripheral benzodiazepine receptor ligand PK 11195 inhibits arthritis in the MRL-lpr mouse model. Rheumatology

Weisgraber, K.H., Roses, A.D., Strittmatter, W.J.(1994). The role of apolipoprotein E in the

Whitman, S.C. (2004). A practical approach to using mice in atherosclerosis research. *Clin* 

Wilms, H., Claasen, J., Röhl, C., Sievers, J., Deuschl, G., & Lucius, R. (2003). Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases:

Wojta, J., Huber, K., & Valent, P. (2003). New aspects in thrombotic research: complement induced switch in mast cells from a profibrinolytic to a prothrombotic phenotype.

Woods, A.A., Linton, S.M. & Davies, M.J. (2003). Detection of HOCl-mediated protein oxidation products in the extracellular matrix of human atherosclerotic plaques.

Xu, P.T., Schmechel, D., Rothrock-Christian, T., Burkhart, D.S., Qiu, H.L., Popko, B., Sullivan, P., Maeda, N, Saunders, A.M., Roses, A.D., & Gilbert, J.R. (1996). Human apolipoprotein E2, E3, and E4 isoform-specific transgenic mice: human-like pattern of glial and neuronal immunoreactivity in central nervous system not observed in wild-

Yang, H., Roberts, J.L., Shi, M.J., Zhou, C., Ballard, B.R., Richardson, A .& Guo, Z.M. (2004). Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide

Zeno, S., Zaaroor, M., Leschiner, S., Veenman, L., & Gavish, M. (2009). CoCl(2) induces apoptosis via the 18kDa translocator protein in U118MG human glioblastoma cells.

Zeno, S., Veenman, L., Katz, Y., Bode, J., Gavish, M., & Zaaroor, M. (2012). The 18 kDa mitochondrial Translocator Protein (TSPO) prevents accumulation of protoporphyrin IX. Involvement of reactive oxygen species. *Curr Molecular Medicine.* 12(4): 494-501.

dismutase and catalase in mice lacking apoliporotein E. *Circ Res*. 95, 1075-1081. Young, C.G., Knight, C., Vickers, K.C., Westbrook, D., Madamanchi, N.R., Runge, M.S., Ischiropoulos, H., & Ballinger, S.W. (2004). Differential effects of exercise on aortic

mitochondria. *Am J Physol Heart Circ Physiol*. 288, H1683-H1689.

evidence from activated microglial cells in vitro. *Neurobiol Dis*. 14:417-24.

viability affected by glutamate. *Pharmacogenet Genomics.* 22:606-19.

kainic acid excitotoxicity. *J Neurosci Res*. 80:129-3.

nervous system. *Curr Opin Lipidol*. 5:110-6.

*Pathophysiol Haemost Thromb.* 33:438-41.

type mice. *Neurobiol Dis*. 3:229-45.

*Neurosci Res*. 50:345-53.

(Oxford). 38:1068-73.

*Biochem Rev.* 25(1), 81-93.

*Biochem.* 370: 729-35.

*Biochem.* 48, 4652-61.


gene expression of glutamate receptors, transporters, and metabolism, and on cell viability affected by glutamate. *Pharmacogenet Genomics.* 22:606-19.

Veiga, S., Azcoitia, I., Garcia-Segura, L.M. (2005). Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity. *J Neurosci Res*. 80:129-3.

116 Lipid Metabolism

*Rev.* 84,1381–478.

*Dermatol*. 140:1010-6.

*Differ*. 8:747-53.

*Lipidol*. 13:119-23.

401.

205.

*Med.* 12(4): 398-412.

*Neuroimmunol*. 42:177-85.

of macrophages. *Proc Natl Acad Sci* U S A. 84:8735-9.

implication in Brain Disease. *Drug Dev Res* 50:355-370

host-defence response. *Curr Pharm Des.* 13, 2385-405.

*Thromb Haemost* 3, 1825-1834.

Stocker, R & Keaney, JF Jr. (2004). Role of oxidative modifications in atherosclerosis. *Physiol* 

Stocker, R & Keaney, J.F. Jr. (2005). New insights on oxidative stress in the artery wall*. J* 

Stoebner, P.E., Carayon, P., Penarier, G., Fréchin, N., Barnéon, G., Casellas, P., Cano, J.P., Meynadier, J., & Meunier, L. (1999). The expression of peripheral benzodiazepine receptors in human skin: the relationship with epidermal cell differentiation. *Br J* 

Stoebner, P.E., Carayon, P., Casellas, P., Portier, M, Lavabre-Bertrand, T., Cuq, P., Cano, J.P., Meynadier, J., & Meunier L. (2001). Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis. *Cell Death* 

Strittmatter, W.J. & Bova Hill ,C. (2002). Molecular biology of apolipoprotein E. *Curr Opin* 

Taupin, V., Toulmond, S., Serrano, A., Benavides, J., & Zavala, F. (1993). Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of pre- and posttraumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. *J* 

Thoenen, H. (1987). Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role

Torres, S.R., Fröde, T.S., Nardi, G.M., Vita, N., Reeb, R., Ferrara, P., Ribeiro-do-Valle, R.M.,Farges, R.C. (2000). Anti-inflammatory effects of peripheral benzodiazepine receptor ligands in two mouse models of inflammation. *Eur J Pharmacol*. 408:199-211. Truskey, G.A., Herrmann, R.A., Kait, J., & Barber, K.M. (1999). Focal increases in vascular cell adhesion molecule-1 and intimal macrophages at atherosclerosis-susceptible sites in the rabbit aorta after short-term cholesterol feeding. *Arterioscler Thromb Vasc Biol*. 19:393-

Veenman, L. & Gavish, M. (2000). Peripheral-type benzodiazepine receptors: Their

Veenman, L. & Gavish, M. (2006). The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development. *Pharmacol Ther*.110, 503-24. Veenman, L., Papadopoulos, V., & Gavish, M. (2007). Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the

Veenman, L., Shandalov, Y., & Gavish, M. (2008). VDAC activation by the 18 kDa translocator protein (TSPO), implications for apoptosis*. J Bioenerg Biomembr.* 40(3):199-

Veenman, L., Gavish, M. (2012). The role of 18 kDa mitochondrial translocator protein (TSPO) in programmed cell death, and effects of steroids on TSPO expression. *Curr Mol* 

Veenman, L., Bode, J., Gaitner, M., Caballero, B., Pe'er, Y., Zeno, S., Kietz, S., Kugler, W., Lakomek, M., Gavish, M. (2012) Effects of 18-kDa translocator protein knockdown on


#### 118 Lipid Metabolism

Zhao, Y., Kuge, Y., Zhao, S., Strauss, W.H., Blankenberg, F.G., & Tamaki, N. (2008). Prolonged high-fat feeding enhances aortic 18F-FDG and 99mTc-annexin A5 uptake in apolipoprotein E-deficient and wild type C57BL/6J mice. *J Nucl Med.* 49, 1707-1714.

**Chapter 6** 

© 2013 Crellin et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Metabolism of Plasma Membrane** 

Paul K. Crellin, Chu-Yuan Luo and Yasu S. Morita

to the growth and survival of the slow-growing pathogens.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52781

**1. Introduction** 

**Lipids in Mycobacteria and Corynebacteria** 

Bacteria of the Corynebacterineae, a suborder of the Actinobacteria, comprise *Mycobacterium*, *Corynebacterium*, *Nocardia*, *Rhodococcus* and other genera. This suborder of high GC gram-positive bacteria includes a number of important human pathogens, such as *Mycobacterium tuberculosis*, *Mycobacterium leprae* and *Corynebacterium diphtheriae,* the causative agents of tuberculosis, leprosy and diphtheria, respectively. *M. tuberculosis* is the most medically significant species, a devastating human pathogen infecting around onethird of the entire human population and responsible for more than 1 million deaths annually. The Corynebacterineae also includes non-pathogenic species such as *Mycobacterium smegmatis*, a saprophytic species, and *Corynebacterium glutamicum*, an industrial workhorse for the production of amino acids and other useful compounds. These relatively fast-growing species serve as useful models to study metabolic processes essential

All these bacteria share a common feature, a distinctive multilaminate cell wall composed of peptidoglycan, complex polysaccharides, and both covalently linked lipids and free lipids/lipoglycans (Fig. 1). Among them, mycolic acids are the hallmark of these species. These long chain α-branched, β-hydroxylated fatty acids are covalently linked to the arabinogalactan polysaccharide layer. This mycolic acid layer is complemented by a glycolipid layer to form an outer "mycomembrane" analogous to the outer membrane of Gram-negative bacteria. [1, 2]. The outer leaflet of the mycomembrane is composed of a variety of lipids including trehalose dimycolates (TDMs), glycopeptidolipids (GPLs), phthiocerol dimycocerosates (PDIMs), sulfolipids, phenolic glycolipids (PGLs), and lipooligosaccharides. Some of these lipids are widely distributed while others are restricted to particular species. For example, TDMs and their structural equivalents are found in both mycobacteria and corynebacteria, while PDIMs and PGLs are restricted to a subset of
