Medizinische Universität Graz - Research portal
Selected Publication:
Lehofer, B.
Impact of high hydrostatic pressure on the structure and molecular dynamics of low-density lipoprotein particles.
[ Dissertation ] Graz University of Technology; 2018. pp.163.
- Authors Med Uni Graz:
- Advisor:
- Prassl Ruth
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- Abstract:
- Low-density lipoprotein (LDL) is a physiologically highly important natural nanoparticle and has caught the attention of researchers for decades. It has an essential physiological role as cholesterol carrier in the blood circulation and is the main cholesterol supplier of peripheral tissue. Despite these essential functions, LDL also plays a crucial role in the progression of atherosclerosis, the basis for various cardiovascular diseases. The LDL particle has a very complex structure and therefore has challenged researchers in elucidating more details about this molecular assembly. Today it is known that LDL has a core-shell structure facilitating the transport of hydrophobic lipids in the aqueous environment of the blood circulation. The core is composed of cholesteryl esters, triglycerides and small amounts of free cholesterol and forms the molecular cargo transported within LDL. This hydrophobic cargo is surrounded by an amphiphilic monolayer of phospholipids and the single protein moiety apolipoprotein B-100 (apoB-100). The scope of this thesis was to further elucidate molecular details of LDL on a dynamical and structural basis in order to provide new knowledge for the development of novel treatment options for cardiovascular diseases. A novel approach by combining different scattering techniques with high hydrostatic pressure (HHP) equipment was applied to characterize LDL on a molecular basis. It could be shown that pressure is a promising tool and an interesting alternative to the use of temperature. Quasielastic neutron scattering (QENS) and elastic incoherent neutron scattering (EINS) were used to investigate dynamical aspects of the LDL samples, whereas small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) were used to probe the structure of LDL under HHP conditions. Different physiologically relevant forms of LDL were probed, namely normolipidemic, triglyceride-rich and oxidized species. It could be shown that motional parameters of different forms of LDL were identical even under HHP conditions, but the proportion of molecular groups participating in the motions was decreased in triglyceride-rich LDL under HHP. Generally, the mean square displacements were reduced for modified forms of LDL under HHP in contrast to normolipidemic LDL, which was not affected in the same way. The structural studies revealed a pressure-induced phase transition of the lipid core of LDL above the transition temperature, which resembled the low temperature state of the macromolecule. This effect was observed in all investigated forms of LDL. The position of the lamellae in the lipid core of LDL seems to be a highly conserved feature, which was not altered through HHP. Ab initio modeling of scattering data revealed anisotropic changes of the overall dimensions of LDL as well as a characteristic flattening of the particle at high hydrostatic pressure conditions. Even under high pressure conditions LDL revealed a reversible behavior concerning structural rearrangements. The knowledge gained in this thesis provides new molecular details about the physiologically highly relevant LDL particle and might support the development of new concepts for the treatment of cardiovascular diseases.