Highlights
- •High-density lipoprotein lipidome was markedly altered in a family with a nonsense mutation in APOA1.
- •Unsaturated lipid species, primarily phosphatidylcholine(34:2), were most strongly affected.
- •Lipids altered by apoA-I deficiency were typically moderately to highly abundant.
- •ApoA-I deficiency strongly affected linoleic acid metabolism.
Background
Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both
apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated
atherosclerosis.
Objective
The objective of this study was to define distinctive patterns in the lipidome of
HDL subpopulations in FAID in relationship to antiatherogenic activities.
Methods
Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian
patients (n = 5) and age-matched healthy normolipidemic Caucasian controls (n = 8),
and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids)
was quantitatively evaluated.
Results
Increased concentrations of numerous molecular species of lysophosphatidylcholine
(up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic
acid (up to 71-fold), and phosphatidylglycerol (up to 20-fold) were detected throughout
all five HDL subpopulations as compared with their counterparts from controls, whereas
concentrations of phosphatidylethanolamine species were decreased (up to 5-fold).
Moderately to highly abundant, within their lipid class, species of phosphatidylcholine,
sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine,
and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency;
their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated
with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid,
glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID.
Conclusion
These data reveal that altered content of specific phospholipid and sphingolipid species
is linked to deficient antiatherogenic properties of HDL in FAID.
Keywords
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References
- Familial hypoalphalipoproteinemia in premature coronary artery disease.Arterioscler Thromb. 1993; 13: 1728-1737
- Familial lipoprotein disorders in patients with premature coronary artery disease.Circulation. 1992; 85: 2025-2033
- Diagnosis and treatment of high density lipoprotein deficiency.Prog Cardiovasc Dis. 2016; 59: 97-106
- Marked HDL deficiency and premature coronary heart disease.Curr Opin Lipidol. 2010; 21: 289-297
- HDL-mediated mechanisms of protection in cardiovascular disease.Cardiovasc Res. 2014; 103: 341-349
- Molecular physiology of reverse cholesterol transport.J Lipid Res. 1995; 36: 211-228
- Genetics of cholesterol efflux.Curr Atheroscler Rep. 2012; 14: 235-246
- The effects of altered apolipoprotein A-I structure on plasma HDL concentration.Trends Cardiovasc Med. 2002; 12: 121-128
- Differential diagnosis of familial high density lipoprotein deficiency syndromes.Atherosclerosis. 2006; 186: 231-239
- Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities.Arterioscler Thromb Vasc Biol. 2013; 33: 2715-2723
- Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis.Pharmacol Rev. 2006; 58: 342-374
- Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome.J Lipid Res. 2014; 55: 2509-2520
- Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency.J Lipid Res. 2008; 49: 349-357
- Fenofibrate Reduces Plasma Cholesteryl Ester Transfer From HDL to VLDL and Normalizes the Atherogenic, Dense LDL Profile in Combined Hyperlipidemia.Arterioscler Thromb Vasc Biol. 1996; 16: 763-772
- A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum.J Lipid Res. 1981; 22: 339-358
- Biological activities of HDL subpopulations and their relevance to cardiovascular disease.Trends Mol Med. 2011; 17: 594-603
- Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler Thromb Vasc Biol. 2007; 27: 1843-1849
- A simple method for the isolation and purification of total lipides from animal tissues.J Biol Chem. 1957; 226: 497-509
- Suppression of Endothelial Cell Apoptosis by High Density Lipoproteins (HDL) and HDL-associated Lysosphingolipids.J Biol Chem. 2001; 276: 34480-34485
- Use of reconstituted metabolic networks to assist in metabolomic data visualization and mining.Metabolomics. 2010; 6: 312-321
- Data, information, knowledge and principle: back to metabolism in KEGG.Nucleic Acids Res. 2014; 42: D199-D205
- Using MetaboAnalyst 3.0 for comprehensive metabolomics data analysis.Curr Protoc Bioinformatics. 2016; 55 (14.10.1-14.10.91)
- A global test for groups of genes: testing association with a clinical outcome.Bioinformatics. 2004; 20: 93-99
- GlobalANCOVA: exploration and assessment of gene group effects.Bioinformatics. 2008; 24: 78-85
- The human plasma lipidome.N Engl J Med. 2011; 365: 1812-1823
- To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase.J Lipid Res. 2014; 55: 1847-1854
- Targeted lipidomics - advances in profiling lysophosphocholine and platelet-activating factor second messengers.Febs J. 2013; 280: 5652-5667
- Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium.Biochem Soc Trans. 2005; 33: 1385-1389
- Review: soluble innate immune pattern-recognition proteins for clearing dying cells and cellular components: implications on exacerbating or resolving inflammation.Innate Immun. 2010; 16: 191-200
- Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway.J Biol Chem. 2003; 278: 45117-45127
- Sphingosine kinase 1 is an intracellular effector of phosphatidic acid.J Biol Chem. 2004; 279: 44763-44774
- Apoptosis and sphingomyelin hydrolysis. The flip side.J Cell Biol. 2000; 150: F5-F7
- Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice.Sci Rep. 2016; 6: 35037
- Generation and biological activities of oxidized phospholipids.Antioxid Redox Signal. 2010; 12: 1009-1059
- Relevance of dietary glycerophospholipids and sphingolipids to human health.Prostaglandins Leukot Essent Fatty Acids. 2015; 101: 41-51
- Conjugated linoleic acid isomers may diminish human macrophages adhesion to endothelial surface.Int J Food Sci Nutr. 2012; 63: 30-35
- Polyunsaturated fatty acid relatively decreases cholesterol content in THP-1 macrophage-derived foam cell: partly correlates with expression profile of CIDE and PAT members.Lipids Health Dis. 2013; 12: 111
- Linoleic acid-rich fats reduce atherosclerosis development beyond its oxidative and inflammatory stress-increasing effect in apolipoprotein E-deficient mice in comparison with saturated fatty acid-rich fats.Br J Nutr. 2005; 94: 896-901
- The role of CDP-diacylglycerol synthetase and phosphatidylinositol synthase activity levels in the regulation of cellular phosphatidylinositol content.J Biol Chem. 1997; 272: 33402-33409
- Sphingolipid transfer proteins defined by the GLTP-fold.Q Rev Biophys. 2015; 48: 281-322
- Intestinal phospholipid and lysophospholipid metabolism in cardiometabolic disease.Curr Opin Lipidol. 2016; 27: 507-512
- Genome-wide association study of serum lipids confirms previously reported associations as well as new associations of common SNPs within PCSK7 gene with triglyceride.J Hum Genet. 2016; 61: 427-433
- HDL metabolism, composition, function and deficiency.Curr Opin Lipidol. 2014; 25: 194-199
- HDL Deficiency due to a New Insertion Mutation (ApoA-I(Nashua)) and Review of the Literature.J Clin Lipidol. 2013; 7: 169-173
- Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA.J Lipid Res. 2015; 56: 703-712
- Effects of plasma infusion on plasma lipids, apoproteins and plasma enzyme activities in familial lecithin: cholesterol acyltransferase deficiency.Eur J Clin Invest. 1984; 14: 122-129
- Familial lecithin:cholesterol acyltransferase deficiency: first-in-human treatment with enzyme replacement.J Clin Lipidol. 2016; 10: 356-367
Article info
Publication history
Published online: February 25, 2019
Accepted:
February 18,
2019
Received:
July 3,
2018
Identification
Copyright
© 2019 National Lipid Association. All rights reserved.
