Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis of Lipoprotein(a).

Rationale: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like lipoprotein and important cardiovascular risk factor whose cognate receptor and intracellular fate remains unknown.

Objective: Our study aimed to determine the intracellular trafficking pathway for Lp(a) and the receptor responsible for its uptake in liver cells.

Methods And Results: Human hepatoma cells were treated with Lp(a) purified from human plasma and Lp(a) uptake studied using Western blot analysis and intracellular localization of Lp(a) by confocal microscopy.

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

Objective: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout.

Chemotherapy Agents Alter Plasma Lipids in Breast Cancer Patients and Show Differential Effects on Lipid Metabolism Genes in Liver Cells.

Cardiovascular complications have emerged as a major concern for cancer patients. Many chemotherapy agents are cardiotoxic and some appear to also alter lipid profiles, although the mechanism for this is unknown. We studied plasma lipid levels in 12 breast cancer patients throughout their chemotherapy.

Triacylglyceride physiology in the short-finned eel, Anguilla australis--the effects of androgen.

The importance of androgens (especially 11-ketotestosterone) during previtellogenesis in eels is well established. In wild pubertal migrants, circulating 11-ketotestosterone levels correlate with a number of morphological and molecular changes. Here, we test the prediction that this correlation represents a causal relationship by artificially raising the levels of circulating 11-ketotestosterone in prepubertal nonmigratory female and pubertal, migratory male short-finned eels (Anguilla australis) using sustained-release hormone implants.

Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus.

Objective: The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration.

Approach And Results: The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations.

Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids.

Elevated levels of lipoprotein (a) [Lp(a)] are a well-established risk factor for developing CVD. While Lp(a) levels are thought to be independent of other plasma lipoproteins, some trials have reported a positive association between Lp(a) and HDL. Whether Lp(a) has a direct effect on HDL is not known.

Triacylglyceride physiology in the short-finned eel, Anguilla australis—changes throughout early oogenesis.

During certain stages in an animal's life cycle, energy requirements may exceed energy intake from the diet. The spawning migration of temperate eels is a textbook example of negative energy balance, forcing these fish to rely on stored fats (triacylglycerides) to provide their muscles with energy for swimming and their growing oocytes with the nutrients needed to develop and support healthy offspring. We predicted broad implications of this great need for endogenous triacylglycerides in terms of their packaging, transport, and ovarian uptake.

Ribose-cysteine increases glutathione-based antioxidant status and reduces LDL in human lipoprotein(a) mice.

Objective: D-ribose-L-cysteine (ribose-cysteine) is a cysteine analogue designed to increase the synthesis of glutathione (GSH). GSH is a cofactor for glutathione peroxidase (GPx), the redox enzyme that catalyses the reduction of lipid peroxides. A low GPx activity and increased oxidised lipids are associated with the development of cardiovascular disease (CVD).

Lipoprotein(a), interleukin-10, C-reactive protein, and 8-year outcome after percutaneous coronary intervention.

Background: This prospective study investigated the association between preprocedural biomarker levels and incident major adverse cardiac events (MACE) in complex patients undergoing percutaneous coronary intervention (PCI) with sirolimus-eluting stenting.

Hypothesis: Lipoprotein(a) (Lp[a]), interleukin-10 (IL-10), and high-sensitivity C-reactive protein (CRP) have long-term prognostic value in patients undergoing PCI.

Methods: Between April 2002 and February 2003, 161 patients were included in the study.

Proteomic analysis of aortae from human lipoprotein(a) transgenic mice shows an early metabolic response independent of atherosclerosis.

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation.

Methods And Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol.

Proteomics of Lipoprotein(a) identifies a protein complement associated with response to wounding.

Lipoprotein(a) [Lp(a)] is a major independent risk factor for cardiovascular disease. Twenty percent of the general population exhibit levels above the risk threshold highlighting the importance for clinical and basic research. Comprehensive proteomics of human Lp(a) will provide significant insights into Lp(a) physiology and pathogenicity.

Homology modeling and functional testing of an ABCA1 mutation causing Tangier disease.

Objective: To investigate the impact of the p.R1068H mutation on the structure and function of the ATP-binding cassette A1 (ABCA1) protein.

Methods: A homology model of the nucleotide binding domains of ABCA1 was constructed to identify the three-dimensional orientation of R1068.

Interaction of the inflammasome genes CARD8 and NLRP3 in abdominal aortic aneurysms.

Objective: Cholesterol crystals have been shown to cause inflammation, and ultimately atherosclerotic lesions through the activation of the NLRP3 inflammasome. As cholesterol crystals have also been found in the walls of patients with abdominal aortic aneurysms (AAA), it is possible that the NLRP3 inflammasome is involved in AAA and genetic variability within this protein complex could alter disease risk. The primary objective of this study was to assess whether there is genetic evidence for a role of the NLRP3 inflammasome in AAA by testing for association of AAA with functional single nucleotide polymorphisms (SNPs) in the CARD8 and NLRP3 genes.

An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations.

The ATP binding cassette transporter (ABCA1) A1 is a key determinant of circulating high density lipoprotein cholesterol (HDL-C) levels. Mutations in ABCA1 are a major genetic contributor to low HDL-C levels within the general population. Following the finding of three different ABCA1 mutations, p.

A gel-based method for purification of apolipoprotein A-I from small volumes of plasma.

We present here a gel-based method for rapid purification of apolipoprotein A-I (apoA-I) from small volumes of human plasma. After isolation of high density lipoprotein from plasma, the apoA-I protein was separated by electrophoresis and the apoA-I band excised from the gel. The apoA-I was then eluted from the gel strip, concentrated, and delipidated ready for use.

Dimyristoylphosphotidylcholine induces conformational changes in apoB that lowers lipoprotein(a).

Lipoprotein(a) [Lp(a)] is assembled by the binding of apolipoprotein B (apoB) lysine residues on LDL to lysine binding sites in apolipoprotein(a) [apo(a)] and the subsequent formation of a disulphide bond between apoB and apo(a). In this study, we induced changes in apoB conformation by adding phospholipids to LDL and tested the effect of the altered apoB conformation on Lp(a) assembly. The addition of dimyristoylphosphatidylcholine (DMPC) to isolated LDL induced a decrease in the alpha-helical content of apoB and increased the immunoreactivity of the apoB C terminus toward monoclonal antibodies in the region.

High-density lipoprotein reduces the human monocyte inflammatory response.

Objective: Whereas the anti-inflammatory effects of high-density lipoprotein (HDL) on endothelial cells are well described, such effects on monocytes are less studied.

Methods And Results: Human monocytes were isolated from whole blood followed by assessment of CD11b activation/expression and cell adhesion under shear-flow. HDL caused a dose-dependent reduction in the activation of CD11b induced by PMA or receptor-dependent agonists.

Lipoprotein(a): biology and clinical importance.

Lipoprotein(a) [Lp(a)] is a unique lipoprotein that has emerged as an independent risk factor for developing vascular disease. Plasma Lp(a) levels above the common cut-off level of 300 mg/L place individuals at risk of developing heart disease particularly if combined with other lipid and thrombogenic risk factors. Studies in humans have shown Lp(a) levels to be hugely variable and under strict genetic control, largely by the apolipoprotein(a) [apo(a)] gene.

Plasma lipoprotein(a) indicates risk for 4 distinct forms of vascular disease.

Background: Increased lipoprotein(a) [Lp(a)] concentrations are predictive for coronary artery disease (CAD). The risk conferred by Lp(a) for other types of vascular disease compared with CAD has not been investigated within a single population. This study aimed to investigate Lp(a) risk association for 4 different types of vascular disease (including CAD) within a predominantly white population.

Promoter haplotype of a new ABCA1 mutant influences expression of familial hypoalphalipoproteinemia.

Mutations in the ATP-binding cassette A1 (ABCA1) transporter cause the high-density lipoprotein (HDL) deficiency syndromes of Tangier disease and familial hypoalphalipoproteinemia (FHA). Between individuals carrying ABCA1 mutations, the expression of FHA can be highly variable. Using denaturing HPLC (dHPLC) and direct promoter sequencing we screened the ABCA1 gene of a family with Tangier disease and variable expression of FHA.

Elastic lamina defects are an early feature of aortic lesions in the apolipoprotein E knockout mouse.

The aortae from male apolipoprotein E knockout (apoE-/-) mice were examined by serial section immunohistochemistry and electron microscopy to determine the continuity of the internal elastic lamina (IEL) and its association with developing intimal lesions. While in this model, defects in the elastic laminae have previously been described beneath advanced xanthomatous lesions, this study demonstrates that disruption of the IEL may be a primary factor in the localization and pathogenesis of intimal lesions in the apoE-/- mouse. IEL defects were found beneath early lesions in animals as young as 8 weeks of age.