The HDL Proteome Watch: Compilation of studies leads to new insights on HDL function

Davidson, W. Sean; Shah, Amy S.; Sexmith, Hannah; Gordon, Scott M.

doi:10.1016/j.bbalip.2021.159072

Cited by 58 publications

(71 citation statements)

References 95 publications

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“…HDL acts as a scaffold and can carry many different plasma proteins, with 251 proteins reproducibly associated with HDL, although each HDL particle can only carry a few other proteins. As reviewed by Davidson, six studies identified 109 HDL proteins showing consistent differences between CHD subjects and healthy controls [ 82 ]. Jin et al assessed the HDL proteome after his-tagged-apoA1 exchange and metal chelate affinity chromatography.…”

Section: Hdl Structure and Cell-free Hdl Function Assaysmentioning

confidence: 99%

HDL Is Not Dead Yet

Lorkowski

Smith

2022

Biomedicines

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High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with coronary heart disease (CHD) in multiple epidemiological studies, but whether HDL is causal or merely associated with CHD is unclear. Recent trials for HDL-raising drugs were either not effective in reducing CHD events or, if beneficial in reducing CHD events, were not conclusive as the findings could be attributed to the drugs’ LDL-reducing activity. Furthermore, the first large Mendelian randomization study did not causally relate HDL-C levels to decreased CHD. Thus, the hypothesis that HDL is protective against CHD has been rightfully challenged. However, subsequent Mendelian randomization studies found HDL characteristics that are causally related to decreased CHD. Many aspects of HDL structure and function, especially in reverse cholesterol transport, may be better indicators of HDL’s protective activity than simply measuring HDL-C. Cholesterol efflux capacity is associated with lower levels of prevalent and incident CHD, even after adjustment for HDL-C and apolipoprotein A-1 levels. Also, subjects with very high levels of HDL-C, including those with rare mutations that disrupt hepatic HDL uptake and reverse cholesterol transport, may be at higher risk for CHD than those with moderate levels. We describe here several cell-based and cell-free in vitro assays of HDL structure and function that may be used in clinical studies to determine which of HDL’s functions are best associated with protection against CHD. We conclude that the HDL hypothesis may need revision based on studies of HDL structure and function, but that the HDL hypothesis is not dead yet.

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Section: Hdl Structure and Cell-free Hdl Function Assaysmentioning

confidence: 99%

HDL Is Not Dead Yet

Lorkowski

Smith

2022

Biomedicines

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“…52 In fact, HDL proteome analysis suggests that nearly half of the 96 commonly identified proteins are related to protease activity or regulation, and nearly all are SERPINs or serine proteases. Further analysis of the HDL proteome 53 revealed that all 13 proteins (along with, unsurprisingly, the 6 Ig's/complement proteins) were represented. All proteins were identified in at least three different studies performed by different labs, and they appeared in the top 10% of proteins most frequently identified.…”

Section: Journal Of Proteome Researchmentioning

confidence: 99%

Morphology and Composition of Immunodiffusion Precipitin Complexes Evaluated via Microscopy and Proteomics

et al. 2021

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New approaches to rapid, simple, in vitro diagnostic immunoassays that do not rely on centralized laboratory facilities are urgently needed for disease diagnosis and to inform treatment strategies. The recent and ongoing COVID-19 pandemic has emphasized that rapid diagnostics are needed to help guide government policies on quarantines, social distancing measures, and community lockdowns. A common approach to developing new immunoassays is to modify existing platforms (e.g., automated ELISA and lateral flow assays) for the new analyte, even though this does not address the drawbacks of existing platforms. An alternate approach is to search for robust assays that have been superseded but could in fact solve important challenges using modern technologies. Immunodiffusion is one such platform based on unique "precipitin ring" patterns formed in gels or paper following interactions between proteins and cognate antibodies in diffusion/reaction systems. Herein, we investigate the microstructure of these precipitin rings using a combination of fluorescence and electron microscopy and also perform a mass spectrometry investigation to determine the proteomic composition of the rings. We observed that the rings were composed of microparticles, which we termed "precipitin complexes", and that these complexes were composed of at least 19 key proteins, including immunoglobulins and complement factors along with a range of plasma proteins, possibly related to immune complexes and/or high-density lipoprotein particles. This information will be useful in developing new in vitro diagnostics using reaction/diffusion systemstechniques that require a single assay step and that only require calibrated length measurements for target protein quantification.

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“…Collectively, these observations indicate that HDL-C levels do not necessarily reflect HDL's cardioprotective effects, indicating the need for HDL metrics of CVD risk that are distinct from HDL-C. HDL carries a wide array of proteins linked to lipoprotein metabolism, inflammation, protease inhibition, and complement regulation (13), suggesting that its protein cargo may influence HDL's cardioprotective properties independently of traditional CVD risk factors. Mass spectrometry-based proteomics demonstrate that ~200 proteins are detected in HDL (14). Low levels of paraoxonase 3 (PON3), one of the HDL proteins, associate with subclinical atherosclerosis (15).…”

Section: Introductionmentioning

confidence: 99%

“…HDL carries a wide array of proteins linked to lipoprotein metabolism, inflammation, protease inhibition, and complement regulation ( 13 ), suggesting that its protein cargo may influence the cardioprotective properties of HDL independently of traditional CVD risk factors. MS-based proteomics demonstrate that ∼200 proteins are detected in HDL ( 14 ). Low levels of paraoxonase (PON) 3, one of the HDL proteins, associate with subclinical atherosclerosis ( 15 ).…”

mentioning

confidence: 99%