Multiple apolipoprotein kinetics measured in human HDL by high-resolution/accurate mass parallel reaction monitoring

Singh, Sasha A; Andraski, Allison B.; Pieper, Brett; Goh, Wilson Wen Bin; Mendivil, Carlos O.; Sacks, Frank M.; Aikawa, Masamichi

doi:10.1194/jlr.d061432

Cited by 37 publications

(140 citation statements)

References 63 publications

(67 reference statements)

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“…Changes in apolipoprotein abundance can now be readily assessed using one or more of a number of strategies including label-free and label-based strategies. (56,57). Quantitative proteomics provides several innovative workflows that are poised to address many of the unknowns of apolipoprotein function and metabolism.…”

Section: Hdl-c Hypothesismentioning

confidence: 99%

The High Density Lipoprotein Cholesterol Hypothesis Revisited

2018

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IntroductionClassical epidemiology has established the incremental contribution of the high-density lipoprotein cholesterol (HDL-C) measure in the assessment of atherosclerotic cardiovascular disease (CVD) risk, yet, genetic epidemiology does not support a causal relationship between HDL-C and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic CVD risk. The reference range of HDL-C is 40-50 mg/dL in men and 50-60 mg/dL in women. However, therapeutic interventions such as niacin, cholesterylester transfer protein (CETP) inhibitors increase HDL-C in patients treated with statins, but have repeatedly failed to reduce CVD events.(1) Clinical trials with pharmacological therapies that increase the cholesterol content of HDL particles have failed to establish this convenient metric as The High Density Lipoprotein Cholesterol Hypothesis Revisited R E V I E W A R T I C L E B ACKGROUND:The strong inverse association of plasma levels of high-density lipoprotein cholesterol (HDL-C) with coronary heart disease (CHD) found in human epidemiological studies led to the development of the 'HDL-C hypothesis', which posits that intervention to raise HDL-C will result in reduced risk of CHD. However, recent evidence has raised doubts about the hypotheses that elevating HDL-C is necessarily therapeutic. Genetic variations that associate with altered HDL-C do not strongly associate with altered cardiovascular disease risk.CONTeNT: HDL-mediated cholesterol efflux from macrophage foam cells or measurements of the flux of cholesterol from macrophages to the liver and feces seem to correlate better with atherosclerotic burden than with HDL-C levels. Thus, it may be time to modify the HDL-C hypothesis to the 'HDL flux hypothesis', where intervention to promote cholesterol efflux and reverse cholesterol transport will reduce CHD risk, regardless of whether it affects plasma HDL-C levels. A deeper understanding of the complex biology of HDL metabolism and its relationship to reverse cholesterol transport and atherothrombotic events is urgently needed. This might lead to biomarkers of HDL flux and functionality that are more informative than simple measurements of HDL-C levels. SUmmARy:It is now clear from recent clinical trial and genetic studies that some approaches to raising HDL-C levels may have no effect on CHD. This suggests the need to evaluate HDL-C-raising therapies in different clinical populations, as well as therapies targeted toward HDL flux and function rather than simply HDL-C elevation. Perhaps moving from a focus on the HDL-C hypothesis to a focus on the HDL flux hypothesis will permit a biologically based reassessment of the optimal therapeutic approach to targeting HDL for reduction in cardiovascular risk.KeywORDS: reverse cholesterol transport, cholesterol efflux capacity, HDL dysfunction, HDL particle size, HDL lipidomics, HD...

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Section: Hdl-c Hypothesismentioning

confidence: 99%

The High Density Lipoprotein Cholesterol Hypothesis Revisited

2018

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“…Label-free employs either spectral counting (the total number peptide-spectrum matches per protein) or the area under the curve of the peptides’ chromatographic peaks [2], under the observation that the more abundant a protein is in the sample, the more likely its peptides are detected and sequenced (Fig. 1d).…”

Section: Unbiased Proteomics Applied To Hdl Biologymentioning

confidence: 99%

“…1a). Some of these studies have specifically addressed whether proteins are differentially localized across HDL size or density fractions [2, 4, 11, 12]. …”

Section: Unbiased Proteomics Applied To Hdl Biologymentioning

confidence: 99%

“…Moreover, LC-MS technology has extended well beyond a tool for identification. Changes in apolipoprotein abundance can now be readily assessed using one or more of a number of strategies including label-free and label-based strategies [2, 3]. Quantitative proteomics provides several innovative workflows that are poised to address many of the unknowns of apolipoprotein function and metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Unbiased and targeted mass spectrometry for the HDL proteome

Singh

Aikawa

2017

Current Opinion in Lipidology

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Purpose of review Mass spectrometry (MS) is an ever evolving technology that is equipped with a variety of tools for protein research. Some lipoprotein studies, especially those pertaining to HDL biology, have been exploiting the versatility of MS to understand HDL function through its proteome. Despite the role of MS in advancing research as a whole however, the technology remains obscure to those without hands on experience, but still wishing to understand it. In this review, we walk the reader through the co-evolution of common MS workflows and HDL research, starting from the basic unbiased MS methods used to profile the HDL proteome to the most recent targeted methods that have enabled an unprecedented view of HDL metabolism. Recent findings Unbiased global proteomics have demonstrated that the HDL proteome is organized into sub-groups across the HDL size fractions providing further evidence that HDL functional heterogeneity is in part governed by its varying protein constituents. Parallel reaction monitoring, a novel targeted MS method, was used to monitor the metabolism of HDL apolipoproteins in humans and revealed that apolipoproteins contained within the same HDL size fraction exhibit diverse metabolic properties. Summary MS provides a variety of tools and strategies to facilitate understanding, through its proteins, the complex biology of HDL.

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“…68 Singh et al from our laboratory, however, demonstrated the ability of PRM to measure <1% tracer enrichment in not only apoA-I from 5 HDL size fractions, but also 6 additional HDL apolipoproteins. 72 Figure 7B demonstrates a PRM scan of the apoA-I peptide, THLAPYSDELR. A magnification of a fragment ion (b4, THLA) shows its isotopes, M0-M3.…”

Section: Selected Reaction Monitoring (Srm) and Parallel Reaction Monmentioning

confidence: 99%

Current Trends and Future Perspectives of State-of-the-Art Proteomics Technologies Applied to Cardiovascular Disease Research

Singh

Aikawa

2016

Circ J

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The ongoing development of MS is in part influenced by the drive to identify and quantify as many proteins as possible in a given sample. 1,15-17 A major challenge in proteomics, however, is that the dynamic range of a typical deep sequencing analysis (5-6 orders in magnitude) does not reflect the more extensive dynamic range of protein abundance that is as extensive as 12 orders in plasma. 18-20 In addition, cytoskeletal and extracellular matrix proteins dominate samples, masking the less abundant transcription factors and signaling molecules that are usually of interest. 1,18,19 Depletion of these highly abundant proteins, such as albumin from plasma, is required to sequence deep into the proteome ( Figure 1C). 21-23 Also, the less abundant proteins can be enriched by cellular fractionation methods such as those that separate cellular compartments or those that use immunopurification strategies ( Figure 1C). 24, 25 The dynamic range capabilities of MS continually improve, but the identification and quantification of low-abundance proteins still depend on sample preparation procedures that shift these low signals into the detection range of the instrument either by depletion and/or enrichment approaches.any developments in the field of proteomics have come from the yeast model system 1-3 and from cancer research ( Figure 1A). In addition, immortalized cells (eg, HeLa, HEK293T, RAW264.7, THP-1) have provided mass spectrometrists ample protein with limited variability across biological replicates, factors that are important to establish technical reproducibility when novel workflows are being developed. The cardiovascular sciences have also influenced and benefited from developments in unbiased and targeted mass spectrometry (MS) approaches ( Figure 1B). Research pertaining to the heart and its metabolism, 4,5 extracellular matrix remodeling 6,7 posttranslational modification in vascular development. 8 lipoprotein content and metabolism, 9-11 and platelet function 12,13 have thrived as a result of the application of MS technologies. Recently, cardiovascular disease research has taken advantage of the readily accessible plasma pool for biomarker-and target-based studies. Tissues affected by heart failure, atherosclerosis and aortic aneurysms are in direct contact with the circulatory system, which increases the likelihood that proteins either causal or consequential to these pathologies can be detected in plasma. The use of mass spectrometry (MS)-dependent protein research is increasing in the cardiovascular sciences. A major reason for this is the versatility of and ability for MS technologies to accommodate a variety of biological questions such as those pertaining to basic research and clinical applications. In addition, mass spectrometers are becoming easier to operate, and require less expertise to run standard proteomics experiments. Nonetheless, despite the increasing interest in proteomics, many non-expert end users may not be as familiar with the variety of mass spectrometric tools and workflows available...

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Multiple apolipoprotein kinetics measured in human HDL by high-resolution/accurate mass parallel reaction monitoring

Cited by 37 publications

References 63 publications

The High Density Lipoprotein Cholesterol Hypothesis Revisited

The High Density Lipoprotein Cholesterol Hypothesis Revisited

Unbiased and targeted mass spectrometry for the HDL proteome

Current Trends and Future Perspectives of State-of-the-Art Proteomics Technologies Applied to Cardiovascular Disease Research

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