- •We have characterized the proteome of HDL in healthy subjects and patients with CETP-D.
- •We identified 79 HDL-associated proteins, 5 of which were newly identified.
- •ApoE, apoC-III, and complement C3 and C4b were significantly increased in HDL of CETP-D.
- •We identified ANGPTL3 as an HDL-associated protein, which was increased in CETP-D.
- •These proteomic changes might be partly responsible for atherogenicity of CETP-D.
We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions.
This study aimed to investigate the protein composition of HDL particles in patients with CETP-D.
Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL.
We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P < .001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P < .01).
We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Clinical Lipidology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the atherosclerosis risk in communities (ARIC) study.Circulation. 2001; 104: 1108-1113
- Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies.Eur Heart J. 2017; 38: 2478-2486
- Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: the EPOCH-JAPAN study.J Clin Lipidol. 2018; 12: 674-684.e5
- Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyper HDL2 cholesterolemia with abnormal cholesteryl ester transferTitle.Am J Cardiol. 1988; 62: 66B-72B
- Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity.Arterioscler Thromb Vasc Biol. 1997; 17: 1053-1059
- Effect of torcetrapib on the progression of coronary atherosclerosis.N Engl J Med. 2007; 356: 1304-1316
- Effects of dalcetrapib in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 367: 2089-2099
- Evacetrapib and cardiovascular outcomes in high-risk vascular disease.N Engl J Med. 2017; 376: 1933-1942
- Effects of anacetrapib in patients with atherosclerotic vascular disease.N Engl J Med. 2017; 377: 1217-1227
- Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.N Engl J Med. 2011; 364: 127-135
- HDL cholesterol efflux capacity and incident cardiovascular events.N Engl J Med. 2014; 371: 2383-2393
- Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.J Clin Invest. 2007; 117: 746-756
- Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond.J Lipid Res. 2013; 54: 2575-2585
- Point mutation (-69 G-->A) in the promoter region of cholesteryl ester transfer protein gene in Japanese hyperalphalipoproteinemic subjects.Arterioscler Thromb Vasc Biol. 2001; 21: 985-990
- Total deficiency of plasma cholesteryl ester transfer protein in subjects homozygous and heterozygous for the intron 14 splicing defect.Biochem Biophys Res Commun. 1990; 170: 1346-1351
- A novel nonsense mutation (G181X) in the human cholesteryl ester transfer protein gene in Japanese hyperalphalipoproteinemic subjects.J Lipid Res. 1996; 37: 2145-2154
- The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.J Clin Invest. 1955; 34: 1345-1353
- Modification of the bicinchoninic acid protein assay to eliminate lipid interference in determining lipoprotein protein content.Anal Biochem. 1992; 204: 332-334
- Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips.Nat Protoc. 2007; 2: 1896-1906
- Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis.J Proteome Res. 2008; 7: 731-740
- Altered activation of endothelial anti-and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling.Circulation. 2013; 127: 891-904
- Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search.Anal Chem. 2002; 74: 5383-5392
- A statistical model for identifying proteins by tandem mass spectrometry.Anal Chem. 2003; 75: 4646-4658
- Improved detection of quantitative differences using a combination of spectral counting and MS/MS total ion current.J Proteome Res. 2013; 12: 1996-2004
- Spectral index for assessment of differential protein expression in shotgun proteomics.J Proteome Res. 2008; 7: 845-854
- Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia.Atherosclerosis. 2000; 152: 271-285
- Accumulation of apolipoprotein E-rich high-density lipoproteins in hyperalphalipoproteinemic human-subjects with plasma cholesteryl ester transfer protein-deficiency.J Clin Invest. 1990; 86: 688-695
- Apolipoprotein C-III: going back to the future for a lipid drug target.Circ Res. 2013; 112: 1405-1408
- Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community.Circulation. 2009; 120: 2414-2420
- Plasma lipid transfer proteins and cardiovascular disease. The framingham heart study.Atherosclerosis. 2013; 228: 230-236
- Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the ludwigshafen risk and cardiovascular health study.Circulation. 2010; 121: 366-374
- Cholesteryl ester transfer protein in patients with coronary heart disease.Eur J Clin Invest. 2010; 40: 616-622
- Genetic variant of the scavenger receptor BI in humans.N Engl J Med. 2011; 364: 136-145
- Particle number analysis of lipoprotein subclasses by gel permeation HPLC in patients with cholesteryl ester transfer protein deficiency.PLoS One. 2018; 13: e0190875
- Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency can not protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins.J Biochem. 1994; 116: 257-262
- VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the cholesterol and recurrent events (CARE) trial.Circulation. 2000; 102: 1886-1892
- Apolipoprotein C-III: understanding an emerging cardiovascular risk factor.Clin Sci (Lond). 2008; 114: 611-624
- Loss-of-function mutations in APOC3, triglycerides, and coronary disease.N Engl J Med. 2014; 371: 22-31
- Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia.N Engl J Med. 2015; 373: 438-447
- The complement system.Cell Tissue Res. 2011; 343: 227-235
- Complement in atherosclerosis: friend or foe?.J Thromb Haemost. 2011; 9: 428-440
- The HDL proteome in acute coronary syndromes shifts to an inflammatory profile.Biochim Biophys Acta. 2012; 1821: 405-415
- The role of ANGPTL3 in controlling lipoprotein metabolism.Endocrine. 2016; 52: 187-193
- Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.N Engl J Med. 2017; 377: 211-221
Published online: January 10, 2019
Accepted: January 7, 2019
Received: July 18, 2018
© 2019 National Lipid Association. All rights reserved.