Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake

Pollard, Ricquita D.; Blesso, Christopher N.; Zabalawi, Manal; Fulp, Brian; Gerelus, Mark; Zhu, Xuewei; Lyons, Erica W.; Nuradin, Nebil; Francone, Omar L.; Li, Xiang-An; Sahoo, Daisy; Thomas, Michael J.; Sorci‐Thomas, Mary G.

doi:10.1074/jbc.m115.646240

Cited by 30 publications

(44 citation statements)

References 94 publications

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“…Therapies aimed at increasing HDL cholesterol in those with low concentrations are under intense investigation in the hope of preventing future cardiovascular events (13)(14)(15). However, more recently, this association has been challenged by studies that suggest that plasma HDL cholesterol is not always an accurate predictor of CVD risk (16)(17)(18)(19)(20)(21). One aspect concerning HDL that remains consistent is its important role in reverse cholesterol transport (RCT) (22).…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

Millar

Duclos

Blesso

2017

Advances in Nutrition

137

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Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their welldocumented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function. Based on preclinical studies that used cell culture and rodent models, it appears that many flavonoids (e.g., anthocyanidins, flavonols, and flavone subclasses) influence RCT and HDL function beyond simple HDL cholesterol concentration by regulating cellular cholesterol efflux from macrophages and hepatic paraoxonase 1 expression and activity. In clinical studies, dietary anthocyanin intake is associated with beneficial changes in serum biomarkers related to HDL function in a variety of human populations (e.g., in those who are hyperlipidemic, hypertensive, or diabetic), including increased HDL cholesterol concentration, as well as HDL antioxidant and cholesterol efflux capacities. However, clinical research on HDL functionality is lacking for some flavonoid subclasses (e.g., flavanols, flavones, flavanones, and isoflavones). Although there has been a tremendous effort to develop HDL-targeted drug therapies, more research is warranted on how the intake of foods or specific nutrients affects HDL function. Adv Nutr 2017;8:226-39.

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Section: Introductionmentioning

confidence: 99%

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

Millar

Duclos

Blesso

2017

Advances in Nutrition

137

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“…Pollard et al (50) have recently suggested that the extracellular matrix protein procollagen C-endopeptidase enhancer protein 2 interacts with SR-BI and enhances SR-BI-mediated HDL-cholesteryl ester uptake. Whether this interaction has an effect on HDL-associated S1P signaling remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Raw data representing the time-fluorescence relationship for each well after ligand addition were exported to Microsoft Excel for subtraction of background fluorescence and data analysis. The final concentrations in each well for each agonist are rHDL and rHDL + S1P (30 µg protein/ml), HDL2 and HDL3 (10, 50, and 200 µg/ml) in RVSM cells and (50,200, and 500 µg/ml) in HEK293, and S1P (0.1, 0.5, and 1 µM). The final concentration of S1P in the culture medium for cells incubated with rHDL + S1P was set at 120 µM as was used in our previous studies (16) to approximate S1P levels in HDL (15).…”

Section: Analysis Of Physical Interaction Between Hdl Receptor Sr-bi mentioning

confidence: 99%

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

Lee

Appleton

El‐Shewy

et al. 2017

Journal of Lipid Research

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Journal of Lipid Research Volume 58, 2017325 interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization. J. Lipid Res. 2017. 58: 325-338.Supplementary key words high density lipoprotein • sphingosine 1-phosphate • protein-fragment complementation assay • scavenger receptor BI • S1P receptorsThe reverse transport of cholesterol from the periphery to the liver is often considered as the hallmark antiatherogenic function of HDL. SR-BI, the first molecularly characterized HDL receptor that plays a critical role in this metabolism, is abundantly expressed in several types of cells and tissue types, including the liver parenchyma, adrenal cortical cells, platelets, endothelial cells, smooth muscle cells, and macrophages. SR-BI facilitates the selective uptake of HDL cholesterol by cells, primarily in the form of cholesteryl esters. SR-BI also mediates the bidirectional flux of unesterified cholesterol and phospholipids between HDL and cells, which leads to an increase in cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains (1-4).Numerous studies have detailed the various signaling pathways generated by the interaction of HDL with cell surface receptors that have been shown to induce myriad Abstract HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDLstimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.-Lee,

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“…79, 80 Uptake, and possibly efflux, is believed to be mediated in part by the presence of an extracellular matrix (ECM) protein called procollagen C-endopeptidase enhancer protein 2 (PCPE2) which contains 2 CUB, complement C1r/C1s, Uegf, Bmp1, domains and a C-terminal netrin-like (NTR) domain. 81, 82 The NTR domain of PCPE2 anchors the protein to heparin sulfate proteoglycans in the ECM, while the CUB domains bind to apoA-I and enhance SR-BI mediated uptake of CE, Figure 2. To have ABCA1-mediated FC efflux from the cell following SR-BI-mediated uptake of CE may appear to be a futile cycle.…”

Section: Membrane Cholesterol and Lipid Raft Microdomainsmentioning

confidence: 99%

Microdomains, Inflammation, and Atherosclerosis

Sorci‐Thomas

Thomas

2016

Circulation Research

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133

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Elevated levels of cholesteryl ester (CE) enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of atherosclerosis. Unregulated uptake of LDL cholesterol by circulating monocytes and other peripheral blood cells takes place through scavenger receptors and over time causes disruption in cellular cholesterol homeostasis. As lipoproteins are taken up, their CE core is hydrolyzed by liposomal lipases to generate free cholesterol (FC). FC can either be re-esterified and stored as CE droplets or shuttled to the plasma membrane for ATP binding cassette transporter A1 (ABCA1) mediated efflux. Since cholesterol is an essential component of all cellular membranes some FC may be incorporated into microdomains or lipid rafts. These platforms are essential for receptor signaling and transduction, requiring rapid assembly and disassembly. ABCA1 plays a major role in regulating microdomain cholesterol and is most efficient when lipid-poor HDL apolipoprotein A-I (apoA-I) packages raft cholesterol into soluble particles that are eventually catabolized by the liver. If FC is not effluxed from the cell, it becomes esterified and CE droplets accumulate. It follows that as the cell accumulates CE, microdomain cholesterol content becomes poorly regulated. This dysregulation leads to prolonged activation of immune cell signaling pathways, resulting in receptor over-sensitization. The availability of HDL apoA-I or other amphipathic α-helix rich apoproteins relieves the burden of excess microdomain cholesterol in immune cells allowing a reduction in immune cell proliferation and infiltration, thereby, stimulating regression of foam cells in the artery. Therefore, cellular balance between FC and CE is essential for proper immune cell function and prevents chronic immune cell overstimulation and proliferation.

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Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake

Cited by 30 publications

References 94 publications

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

Microdomains, Inflammation, and Atherosclerosis

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