PCPE2: Expression of multifunctional extracellular glycoprotein associated with diverse cellular functions.

Procollagen C-endopeptidase enhancer 2, known as PCPE2 or PCOC2 (gene name, PCOLCE2) is a glycoprotein that resides in the extracellular matrix, and is similar in domain organization to PCPE1/PCPE, PCOC1 (PCOLCE1/PCOLCE). Due to the many similarities between the two related proteins, PCPE2 has been assumed to have biological functions similar to PCPE. PCPE is a well-established enhancer of procollagen processing activating the enzyme, BMP-1.

Scavenger receptor class B type I is required for efficient glucose uptake and metabolic homeostasis in adipocytes.

Obesity is a worldwide epidemic and places individuals at a higher risk for developing comorbidities that include cardiovascular disease and type 2 diabetes. Adipose tissue contains adipocytes that are responsible for lipid metabolism and reducing misdirected lipid storage. Adipocytes facilitate this process through insulin-mediated uptake of glucose and its subsequent metabolism into triglycerides for storage.

Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.

Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels.

Myeloperoxidase Inhibition Ameliorates Plaque Psoriasis in Mice.

Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase contributes to skin pathology. In this study, we used the Aldara (Imiquimod) cream model of plaque psoriasis in mice to assess myeloperoxidase inhibition for treating psoriatic skin lesions.

Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake.

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)-mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage.

Approach And Results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI- mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI-mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI-mediated HDL-C uptake is unknown.

Enterically derived high-density lipoprotein restrains liver injury through the portal vein.

The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL subspecies form, in complex with lipopolysaccharide (LPS)-binding protein (LBP).

The ins and outs of lipid rafts: functions in intracellular cholesterol homeostasis, microparticles, and cell membranes: Thematic Review Series: Biology of Lipid Rafts.

Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts.

Endothelial Rap1 (Ras-Association Proximate 1) Restricts Inflammatory Signaling to Protect From the Progression of Atherosclerosis.

Objective: Small GTPase Rap1 (Ras-association proximate 1) is a novel, positive regulator of NO release and endothelial function with a potentially key role in mechanosensing of atheroprotective, laminar flow. Our objective was to delineate the role of Rap1 in the progression of atherosclerosis and its specific functions in the presence and absence of laminar flow, to better define its role in endothelial mechanisms contributing to plaque formation and atherogenesis. Approach and Results: In a mouse atherosclerosis model, endothelial Rap1B deletion exacerbates atherosclerotic plaque formation.

Integrating Mouse and Human Genetic Data to Move beyond GWAS and Identify Causal Genes in Cholesterol Metabolism.

Identifying the causal gene(s) that connects genetic variation to a phenotype is a challenging problem in genome-wide association studies (GWASs). Here, we develop a systematic approach that integrates mouse liver co-expression networks with human lipid GWAS data to identify regulators of cholesterol and lipid metabolism. Through our approach, we identified 48 genes showing replication in mice and associated with plasma lipid traits in humans and six genes on the X chromosome.

Recombinant LCAT (Lecithin:Cholesterol Acyltransferase) Rescues Defective HDL (High-Density Lipoprotein)-Mediated Endothelial Protection in Acute Coronary Syndrome.

Objective- Aim of this study was to evaluate changes in LCAT (lecithin:cholesterol acyltransferase) concentration and activity in patients with an acute coronary syndrome, to investigate if these changes are related to the compromised capacity of HDL (high-density lipoprotein) to promote endothelial nitric oxide (NO) production, and to assess if rhLCAT (recombinant human LCAT) can rescue the defective vasoprotective HDL function. Approach and Results- Thirty ST-segment-elevation myocardial infarction (STEMI) patients were enrolled, and plasma was collected at hospital admission, 48 and 72 hours thereafter, at hospital discharge, and at 30-day follow-up. Plasma LCAT concentration and activity were measured and related to the capacity of HDL to promote NO production in cultured endothelial cells.

Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis.

Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated.

Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis.

Regulatory T (Treg) cells contribute to the anti-inflammatory response during atherogenesis. Here we show that during atherogenesis Treg cells lose Foxp3 expression and their immunosuppressive function, leading to the conversion of a fraction of these cells into T follicular helper (Tfh) cells. We show that Tfh cells are pro-atherogenic and that their depletion reduces atherosclerosis.

High-Density Lipoprotein Functionality as a New Pharmacological Target on Cardiovascular Disease: Unifying Mechanism That Explains High-Density Lipoprotein Protection Toward the Progression of Atherosclerosis.

The formation of the atherosclerotic plaque that is characterized by the accumulation of abnormal amounts of cholesterol-loaded macrophages in the artery wall is mediated by both inflammatory events and alterations of lipid/lipoprotein metabolism. Reverse transport of cholesterol opposes the formation and development of atherosclerotic plaque by promoting high density lipoprotein (HDL)-mediated removal of cholesterol from peripheral macrophages and its delivery back to the liver for excretion into the bile. Although an inverse association between HDL plasma levels and the risk of cardiovascular disease (CVD) has been demonstrated over the years, several studies have recently shown that the antiatherogenic functions of HDL seem to be mediated by their functionality, not always associated with their plasma concentrations.

A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state.

Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high-density lipoprotein (HDL) structure and metabolism, probably mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood, as lipid-free apoA-I has been notoriously resistant to high-resolution structural study. Published models from low-resolution techniques share certain features but vary considerably in shape and secondary structure.

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood.

Rationale: Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective because of UCP1 (uncoupling protein 1)-dependent thermogenesis.

Objective: We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression.