| 1. |
- Nilsson, Oktawia, et al.
(författare)
-
Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux
- 2021
-
Ingår i: Journal of Lipid Research. - 0022-2275. ; 62
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogendeuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.
|
|
| 2. |
- Nilsson, Oktawia, et al.
(författare)
-
Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux
- 2021
-
Ingår i: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.
|
|
| 3. |
- Waldie, Sarah, et al.
(författare)
-
ApoE and ApoE Nascent-Like HDL Particles at Model Cellular Membranes : Effect of Protein Isoform and Membrane Composition
- 2021
-
Ingår i: Frontiers in Chemistry. - : Frontiers Media S.A.. - 2296-2646. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body.
|
|
| 4. |
- Waldie, Sarah, et al.
(författare)
-
Structure of Lipoproteins and Their Capacity for Lipid Exchange : Relevance for Development of Atherosclerosis and its Treatment by HDL Therapy
- 2021
-
Ingår i: Management of Dyslipidemia. - : InTech. - 9781839685088 - 9781839685071 - 9781839685095
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis, the largest killer in the western world, arises from build-up of plaques at the artery walls and can result in cardiovascular disease. Low- and high-density lipoproteins are involved in the disease development by depositing and removing lipids to and from macrophages at the artery wall. These processes are complex and not fully understood. Thus, determining the specific roles of the different lipoprotein fractions involved is of fundamental importance for the treatment of the disease. In this chapter, we present the state of the art in lipoprotein structure with focus on the comparison between normolipidemic and hypertriglyceridemic individuals. Then we discuss lipid transfer between lipoproteins and receptor-free cellular membranes. Although these models lack any receptor, key clinical observations are mirrored by these, including increased ability of HDL to remove lipids, in contrast to the ability of LDL to deposit them. Also effects of saturated and unsaturated lipids in the presence and absence of cholesterol are revised. These models can then be used to understand the difference in functionality of lipoproteins from individuals showing different lipid profiles and have the potential to be used also for the development of new HDL therapies.
|
|
