**9. References**


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[24] Laggner P and Kostner GM (1978) Thermotropic changes in the surface structure of lipoprotein B from human-plasma low-density lipoproteins. A spin-label study. Eur.J.Biochem. 84: 227-232.

16 Lipoproteins – Role in Health and Diseases

Nature 417: 750-754.

Immunology 12: 204-212.

[9] Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis.

[10] Hurt-Camejo E, Camejo G, Sartipy P (2000) Phospholipase A2 and small, dense low-

[11] Williams KJ and Tabas I (2005) Lipoprotein retention--and clues for atheroma

[12] Hansson GK and Hermansson A (2011) The immune system in atherosclerosis. Nature

[13] Kostner, G. M. and Laggner, P. (1989) in Human Plasma Lipoproteins - Clinical Biochemistry, Principles, Methods, Applications 3 (Fruchart, J. C. and Shepherd, J.,

[14] Hevonoja T, Pentikainen MO, Hyvonen MT, Kovanen PT, Ala-Korpela M (2000) Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL [In Process Citation]. Biochim.Biophys.Acta 1488: 189-210. [15] Chapman MJ, Laplaud PM, Luc G, Forgez P, Bruckert E, Goulinet S, Lagrange D (1988) Further resolution of the low density lipoprotein spectrum in normal human plasma: physicochemical characteristics of discrete subspecies separated by density gradient

[16] Nigon F, Lesnik P, Rouis M, Chapman MJ (1991) Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL

[17] Dejager S, Bruckert E, Chapman MJ (1993) Dense low lipoprotein subspecies with diminished oxidative resistance predominate in combined hyperlipidemia. J.Lipid Res.

[18] Schuster B, Prassl R, Nigon F, Chapman MJ, Laggner P (1995) Core lipid structure is a major determinant of the oxidative resistance of low density lipoprotein.

[19] Murtola T, Vuorela TA, Hyvonen MT, Marrink SJ, Karttunen M, Vattulainen I (2011) Low density lipoprotein: structure, dynamics, and interactions of apoB-100 with lipids.

[20] Segrest JP, Jones MK, De Loof H, Dashti N (2001) Structure of apolipoprotein B-100 in

[21] Sommer A, Prenner E, Gorges R, St³tz H, Grillhofer H, Kostner GM, Paltauf F, Hermetter A (1992) Organization of phosphatidylcholine and sphingomyelin in the surface monolayer of low density lipoprotein and lipoprotein(a) as determined by time-

[22] Atkinson D, Deckelbaum RJ, Small DM, Shipley GG (1977) Structure of human plasma low-density lipoproteins: Molecular organization of the central core.

[23] Laggner P, Degovics G, Müller KW, Glatter O, Kostner GM, Holasek A (1977) Molecular packing and fluidity of lipids in human serum low density lipoproteins.

density lipoprotein. Curr.Opin.Lipidol. 11: 465-471.

regression. Arterioscler.Thromb.Vasc.Biol. 25: 1536-1540.

eds.), pp. 23-54, Walter de Gruyter, Berlin - New York.

ultracentrifugation. J.Lipid Res. 29: 442-458.

receptor. J.Lipid Res. 32, 1741-1753.

Proc.Natl.Acad.Sci.USA 92: 2509-2513.

Proc.Natl.Acad.Sci.USA 74: 1042-1046.

Hoppe-Seyler's Z.Physiol.Chem. 358: 771-778.

low density lipoproteins. J.Lipid Res. 42: 1346-1367.

resolved fluorometry. J.Biol.Chem. 267: 24217-24222.

Soft Matter 7: 8135-8141.

34, 295-308.


	- [41] Laggner P, Kostner GM, Degovics G, Worcester DL (1984) Structure of the cholesteryl ester core of human plasma low density lipoproteins: Selective deuteration and neutron small- angle scattering. Proc.Natl.Acad.Sci.USA 81: 4389-4393.
	- [42] Sherman MB, Orlova EV, Decker GL, Chiu W, Pownall HJ (2003) Structure of triglyceride-rich human low-density lipoproteins according to cryoelectron microscopy. Biochemistry 42: 14988-14993.
	- [43] Coronado-Gray A and Van Antwerpen R (2005) Lipid composition influences the shape of human low density lipoprotein in vitreous ice. Lipids 40: 495-500.
	- [44] Prassl R, Pregetter M, Amenitsch H, Kriechbaum M, Schwarzenbacher R, Chapman JM, Laggner P (2008) Low density lipoproteins as circulating fast temperature sensors. PLoS ONE 3: e4079 .
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	- [46] Pregetter M, Prassl R, Schuster B, Kriechbaum M, Nigon F, Chapman J, Laggner P (1999) Microphase separation in low density lipoproteins. Evidence for a fluid triglyceride core below the lipid melting transition. J.Biol.Chem. 274: 1334-1341.
	- [47] Small, D. M. (1986) in The Physical Chemistry of Lipids From Alkanes to Phospholipids pp. 395-473, Plenum Press, New York and London.
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	- [49] Morton RE and Parks JS (1996) Plasma cholesteryl ester transfer activity is modulated by the phase transition of the lipoprotein core. J.Lipid Res. 37: 1915-1923.
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	- [51] Esterbauer H, Dieber-Rotheneder M, Waeg G, Striegl G, Jürgens G (1990) Biochemical, Structural, and Functional Properties of Oxidized Low-Density Lipoprotein. Chem.Res.Toxicol. 3: 77-92.
	- [52] Chen S-H, Yang C-Y, Chen PF, Setzer D, Tanimura M, Li W-H, Gotto AM, Jr., Chan L (1986) The complete cDNA and amino acid sequence of human apolipoprotein B-100. J.Biol.Chem. 261: 2918-2921.
	- [53] Knott TJ, Pease RJ, Powell LM, Wallis SC, Rall SC, Innerarity TL, Blackhart B, Taylor WH, Marcel Y, Milne R, Johnson D, Fuller M, Lusis AJ, McCarthy BJ, Mahley RW, Levy-Wilson B, Scott J (1986) Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature 323: 734-738.
	- [54] Phillips ML and Schumaker VN (1989) Conformation of apolipoprotein B after lipid extraction of low-density lipoproteins attached to an electron microscope grid. J.Lipid Res. 30: 415-422.
	- [55] Johs A, Hammel M, Waldner I, May RP, Laggner P, Prassl R (2006) Modular structure of solubilized human apolipoprotein B-100. Low resolution model revealed by small angle neutron scattering. J.Biol.Chem. 281: 19732-19739.

[56] Chatterton JE, Phillips ML, Curtiss LK, Milne RW, Marcel YL, Schumaker VN (1991) Mapping apolipoprotein B on the low density lipoprotein surface by immunoelectron microscopy. J.Biol.Chem. 266: 5955-5962.

18 Lipoproteins – Role in Health and Diseases

Biochemistry 42: 14988-14993.

ONE 3: e4079 .

[41] Laggner P, Kostner GM, Degovics G, Worcester DL (1984) Structure of the cholesteryl ester core of human plasma low density lipoproteins: Selective deuteration and neutron

[42] Sherman MB, Orlova EV, Decker GL, Chiu W, Pownall HJ (2003) Structure of triglyceride-rich human low-density lipoproteins according to cryoelectron microscopy.

[43] Coronado-Gray A and Van Antwerpen R (2005) Lipid composition influences the shape

[44] Prassl R, Pregetter M, Amenitsch H, Kriechbaum M, Schwarzenbacher R, Chapman JM, Laggner P (2008) Low density lipoproteins as circulating fast temperature sensors. PLoS

[45] Liu Y, luo D, Atkinson D (2010) Human LDL core cholesterol ester packing: 3D image

[46] Pregetter M, Prassl R, Schuster B, Kriechbaum M, Nigon F, Chapman J, Laggner P (1999) Microphase separation in low density lipoproteins. Evidence for a fluid

[48] Lusa S and Somerharju P (1998) Degradation of low-density-lipoprotein cholesterol esters by lysosomal lipase in-vitro - effect of core physical state and basis of species

[49] Morton RE and Parks JS (1996) Plasma cholesteryl ester transfer activity is modulated

[50] Zechner R, Kostner GM, Dieplinger H, Degovics G, Laggner P (1984) In vitro modification of the chemical composition of human plasma low-density lipoproteins:

[52] Chen S-H, Yang C-Y, Chen PF, Setzer D, Tanimura M, Li W-H, Gotto AM, Jr., Chan L (1986) The complete cDNA and amino acid sequence of human apolipoprotein B-100.

[53] Knott TJ, Pease RJ, Powell LM, Wallis SC, Rall SC, Innerarity TL, Blackhart B, Taylor WH, Marcel Y, Milne R, Johnson D, Fuller M, Lusis AJ, McCarthy BJ, Mahley RW, Levy-Wilson B, Scott J (1986) Complete protein sequence and identification of structural

[54] Phillips ML and Schumaker VN (1989) Conformation of apolipoprotein B after lipid extraction of low-density lipoproteins attached to an electron microscope grid. J.Lipid

[55] Johs A, Hammel M, Waldner I, May RP, Laggner P, Prassl R (2006) Modular structure of solubilized human apolipoprotein B-100. Low resolution model revealed by small

Effects on morphology and thermal properties. Chem.Phys.Lipids 36: 111-119. [51] Esterbauer H, Dieber-Rotheneder M, Waeg G, Striegl G, Jürgens G (1990) Biochemical, Structural, and Functional Properties of Oxidized Low-Density Lipoprotein.

by the phase transition of the lipoprotein core. J.Lipid Res. 37: 1915-1923.

triglyceride core below the lipid melting transition. J.Biol.Chem. 274: 1334-1341. [47] Small, D. M. (1986) in The Physical Chemistry of Lipids - From Alkanes to

small- angle scattering. Proc.Natl.Acad.Sci.USA 81: 4389-4393.

of human low density lipoprotein in vitreous ice. Lipids 40: 495-500.

reconstruction and SAXS simulation studies. J Lipid Res 51.

selectivity. Bba-Lipid Lipid Metab 1389: 112-122.

domains of human apolipoprotein B. Nature 323: 734-738.

angle neutron scattering. J.Biol.Chem. 281: 19732-19739.

Chem.Res.Toxicol. 3: 77-92.

J.Biol.Chem. 261: 2918-2921.

Res. 30: 415-422.

Phospholipids pp. 395-473, Plenum Press, New York and London.


	- [70] Corbin IR, Li H, Chen J, Lund-Katz S, Zhou R, Glickson JD, Zheng G (2006) Lowdensity lipoprotein nanoparticles as magnetic resonance imaging contrast agents. Neoplasia 8: 488-498.
	- [71] Chen LC, Chang CH, Yu CY, Chang YJ, Hsu WC, Ho CL, Yeh CH, Luo TY, Lee TW, Ting G (2007) Biodistribution, pharmacokinetics and imaging of Re-188-BMEDAlabeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model. Nuclear Medicine and Biology 34: 415-423.
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	- [73] Zhang ZH, Chen J, Ding LL, Jin HL, Lovell JF, Corbin IR, Cao WG, Lo PC, Yang M, Tsao MS, Luo QM, Zheng G (2010) HDL-Mimicking Peptide-Lipid Nanoparticles with Improved Tumor Targeting. Small 6: 430-437.
	- [74] Prassl R, Chapman JM, Nigon F, Sara M, Eschenburg S, Betzel C, Saxena A, Laggner P (1996) Crystallization and preliminary X-ray analysis of a low density lipoprotein from human plasma. J.Biol.Chem. 271: 28731-28733.

**New Insights into the Assembly and Metabolism of ApoB-Containing Lipoproteins from** *in vivo* **Kinetic Studies: Results on Healthy Subjects and Patients with Chronic Kidney Disease** 

Benjamin Dieplinger and Hans Dieplinger

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51865

**1. Introduction** 

20 Lipoproteins – Role in Health and Diseases

Neoplasia 8: 488-498.

[70] Corbin IR, Li H, Chen J, Lund-Katz S, Zhou R, Glickson JD, Zheng G (2006) Lowdensity lipoprotein nanoparticles as magnetic resonance imaging contrast agents.

[71] Chen LC, Chang CH, Yu CY, Chang YJ, Hsu WC, Ho CL, Yeh CH, Luo TY, Lee TW, Ting G (2007) Biodistribution, pharmacokinetics and imaging of Re-188-BMEDAlabeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma

[72] Zheng G, Chen J, Li H, Glickson JD (2005) Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and

[73] Zhang ZH, Chen J, Ding LL, Jin HL, Lovell JF, Corbin IR, Cao WG, Lo PC, Yang M, Tsao MS, Luo QM, Zheng G (2010) HDL-Mimicking Peptide-Lipid Nanoparticles with

[74] Prassl R, Chapman JM, Nigon F, Sara M, Eschenburg S, Betzel C, Saxena A, Laggner P (1996) Crystallization and preliminary X-ray analysis of a low density lipoprotein from

ascites mouse model. Nuclear Medicine and Biology 34: 415-423.

therapeutic agents. Proc.Natl.Acad.Sci.U.S.A 102: 17757-17762.

Improved Tumor Targeting. Small 6: 430-437.

human plasma. J.Biol.Chem. 271: 28731-28733.

Lipoproteins are complexes consisting of a lipid core of mainly triglycerides and cholesterol esters surrounded by a surface monolayer of phospholipids, free cholesterol and specific protein components named apolipoproteins [1]. Most apolipoproteins undergo complex exchange reactions and serve many metabolic functions including transport, enzyme cofactors and receptor ligands. Except for the covalently linked apolipoprotein(a) apolipoproteinB-100 (apo(a)-apoB) complex in Lipoprotein(a) [Lp(a)], apolipoproteins are non-covalently associated with each other and the lipid core.

Lipoprotein disorders are often associated with cardiovascular disease (CVD), atherosclerosis and other organ dysfunctions [2, 3]. To prevent and treat these diseases and to fully understand their cause, it is necessary to characterise the underlying metabolic disorders [1]. The conventional initial approach to do this is by measuring concentrations of plasma lipids or apolipoproteins. However, abnormal concentrations of lipids and apolipoproteins can result from changes in the production, conversion or catabolism of lipoprotein particles. Therefore, although static measurements and functional assays are important techniques to gain first in vivo functional insights, it is necessary to study their metabolic pathway to understand the complexity of lipoprotein function and pathophysiology [4, 5].

Animal models cannot sufficiently replace human studies to explore lipoprotein metabolism due to substantial species specificity. This holds particularly true for conventional

© 2012 Dieplinger and Dieplinger, 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. © 2012 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, and reproduction in any medium, provided the original work is properly cited.

laboratory animals such as mice and rats which – unless genetically modified or induced by special diet - do not develop atherosclerosis (see review [6]). The same argument is valid for investigations using cellular model systems. Since the liver is the central organ responsible for lipoprotein metabolism and primary human hepatocytes are of only limited use in research, most cellular studies in lipoprotein metabolism have been conducted in human hepatoma cells lines. These lines express, secrete and assemble a lipoprotein pattern which is substantially different from the respective human counterpart [7].

For all these reasons, the in vivo investigation of metabolic pathways in human subjects is the ultimate approach to elucidate physiological or pathological functions of metabolites in the human body. Historically, such human kinetic studies were performed using radioactive tracers; this methodology is, however, nowadays of only restricted use. Therefore, stableisotope tracer kinetic studies in human subjects with clear advantages regarding safety and technical issues have replaced the radiotracer methods to become an important research tool for achieving a quantitative understanding of the dynamics of metabolic processes in vivo.

The aim of this review is to shortly describe the methodology and illustrate how the approach has expanded our understanding of physiological mechanisms as well as the pathogenesis of disorders of human lipoprotein metabolism. We will then specifically address the assembly mechanism of the atherogenic Lp(a) complex and focus on the kinetics of apoB-containing lipoproteins in patients with chronic kidney disease. This patient group is well-known for its high risk for atherosclerotic complications and a 10- to 20-fold increased cardiovascular mortality compared to the general population [8].
