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Lipoproteomics: Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lipoprotein particles act as lipid transporters in the blood stream, and measuring cholesterol content in specific subclasses of lipoprotein particles has long been, and still is, a frequently used tool to estimate the risk of cardiovascular disease (CVD). High-density lipoprotein (HDL) is a subclass of lipoproteins often regarded as providing protection against CVD via several functions including reverse cholesterol transport and anti-inflammatory capacities. However, the precise relationship between HDL cholesterol levels and health outcome is still unclear. Lately, new approaches to study HDL composition and function have therefore become more important.

HDL function is to a large extent dependent on its proteome, containing more than 100 proteins. Investigating the proteome in individuals with altered gene expression for HDL-associated proteins or with known exposure to environmental contaminants may reveal new insights into how HDL metabolism is affected by various factors. This is of interest in order to better understand the role of HDL in CVD.

Papers I and II focus on two different mutations in a structural HDL protein, apolipoprotein A-I (L202P and K131del), and one mutation in the scavenger receptor class B-1 (P297S), which is involved in selective lipid uptake of cholesterol mainly into hepatocytes and adrenal cells. The HDL proteome was analyzed using two-dimensional gel electrophoresis and mass spectrometry. The L202P mutation was identified in HDL of the heterozygote carriers together with a significant decrease of apolipoprotein E and increased zinc-alpha-2-glycoprotein. By contrast, the second apolipoprotein AI mutation (K131del) was associated with significantly elevated alpha-1-antitrypsin and transthyretin levels. Protein analyses of the scavenger receptor class B1 P297S heterozygotes showed a significant increase in HDL apoL-1 along with increased free apoE. The carriers showed no difference in antioxidative capability but a significant increase in apoA-I methionine oxidation.

Papers III and IV focus on persistent organic pollutants that may influence HDL composition and function. These compounds accumulate in humans, and exposure has been linked to an increased risk of CVD. To provide a better understanding of the HDL system in relation to pollutants, a population living in a contaminated area was studied. Persistent organic pollutants in isolated HDL were quantified using high-resolution gas chromatography mass spectrometry and significantly increased levels were found in individuals with CVD as compared to healthy controls. Furthermore, there was a significant negative association between the pollutants and paraoxonase-1 anti-oxidant activity. Studying the proteome with nano-liquid chromatography tandem mass spectrometry led to the identification of 118 proteins in HDL, of which ten were significantly associated with the persistent organic pollutants.

In summary, the present studies demonstrate protein pattern alterations in HDL associated with inherited genetic variants or pollutant exposure. The studies also provide a set of methods that are useful tools to further comprehend the complexity of lipoprotein metabolism and function. The results are important in order to improve our understanding of HDL in CVD and to explain an increased risk of CVD associated with exposure to organic pollutants.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 56 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1531
National Category
Biochemistry and Molecular Biology Medicinal Chemistry Pharmacology and Toxicology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medical Genetics
Identifiers
URN: urn:nbn:se:liu:diva-131643DOI: 10.3384/diss.diva-131643ISBN: 9789176857090 (print)OAI: oai:DiVA.org:liu-131643DiVA: diva2:998782
Public defence
2016-11-04, Birgittasalen, Hälsans hus, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-09-30 Created: 2016-09-30 Last updated: 2016-10-04Bibliographically approved
List of papers
1. ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
Open this publication in new window or tab >>ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
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2014 (English)In: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 8, no 3-4, 241-250 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Mutations in apolipoprotein A-I (apoA-I) may affect plasma high-density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA-I variants. This study investigates whether the apoA-I mutations, apoA-I(L202P) and apoA-I(K131del) , are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition.

EXPERIMENTAL DESIGN: Plasma HDL of heterozygotes for either apoA-I(L202P) or apoA-I(K131del) and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS.

RESULTS: ApoA-I peptides containing apoA-I(L202P) or apoA-I(K131del) were identified in HDL from heterozygotes. The apoA-I(L202P) mutant peptide was less abundant than wild-type peptide while the apoA-I(K131del) mutant peptide was more abundant than wild-type peptide in the heterozygotes. Two-dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA-I(L202P) carriers contained less apoE and more zinc-α-2-glycoprotein while HDL from the apoA-I(K131del) heterozygotes contained more alpha-1-antitrypsin and transthyretin.

CONCLUSIONS AND CLINICAL RELEVANCE: Both apoA-I(L202P) and apoA-I(K131del) were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild-type apoA-I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-105992 (URN)10.1002/prca.201300014 (DOI)000334251600013 ()24273187 (PubMedID)
Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2017-12-05
2. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
Open this publication in new window or tab >>Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
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2015 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1851, no 12, 1587-1595 p.Article in journal (Refereed) Published
Abstract [en]

The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.

Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.

Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.

The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-122723 (URN)10.1016/j.bbalip.2015.09.006 (DOI)000364252800008 ()26454245 (PubMedID)
Note

Funding agencies: EUs Sixth Framework Program [037631]; European Union [FP7-603091-2]; CardioVascular Research Initiative [CVON2011-16]; Research Council of South East Sweden [FORSS-3755]; County Council of Ostergotland (C-ALF); Faculty of Health Sciences in Linkoping; Ven

Available from: 2015-11-18 Created: 2015-11-18 Last updated: 2017-12-01
3. Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
Open this publication in new window or tab >>Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
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2014 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 65, 93-9 p.Article in journal (Refereed) Published
Abstract [en]

Persistent organic pollutants (POPs) are lipophilic environmental toxins that have been associated with cardiovascular disease (CVD) and cancer. The aim of this study was to investigate the concentrations of POPs in human high and low/very low-density lipoproteins (HDL and LDL/VLDL) and the possible association with CVD and cancer occurrence in individuals living in a contaminated area. Lipoproteins from 28 individuals (7 healthy controls, 8 subjects with cancer, 13 subjects with CVD) were isolated and the fraction-specific concentration of 20 different POPs was analyzed by high resolution gas chromatography/high resolution mass spectrometry. The activity of Paraoxonase 1 (PON1), an anti-oxidant in HDL, was determined in plasma of these 28 subjects and additional 50 subjects from the same area excluding diseases other than cancer or CVD. Fourteen polychlorinated biphenyls (PCBs) and three organochlorine pesticides were detected, and especially highly chlorinated PCBs were enriched in lipoproteins. Significantly higher concentrations of POPs were found among individuals with CVD or cancer compared to controls. Principal component analyses showed that POP concentrations in HDL were more associated with CVD, while POP concentrations in LDL/VLDL were more associated with cancer. PON1 activity was negatively correlated to sumPCB and a co-variation between decreased arylesterase-activity, increased PCB concentrations and CVD was found. This study shows that POPs are present in lipoproteins and were more abundant in individuals with CVD or cancer compared to healthy controls. The results also indicate that PCB exposure is accompanied by reduced PON1 activity that could impair the HDL function to protect against oxidation.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Clinical Medicine Other Basic Medicine
Identifiers
urn:nbn:se:liu:diva-104755 (URN)10.1016/j.envint.2013.12.017 (DOI)000334728500010 ()24472825 (PubMedID)
Available from: 2014-02-25 Created: 2014-02-25 Last updated: 2017-12-05

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