Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions.

Science.gov (United States)

Wang, Shengjun; Mao, Yang; Narimatsu, Yoshiki; Ye, Zilu; Tian, Weihua; Goth, Christoffer K; Lira-Navarrete, Erandi; Pedersen, Nis B; Benito-Vicente, Asier; Martin, Cesar; Uribe, Kepa B; Hurtado-Guerrero, Ramon; Christoffersen, Christina; Seidah, Nabil G; Nielsen, Rikke; Christensen, Erik I; Hansen, Lars; Bennett, Eric P; Vakhrushev, Sergey Y; Schjoldager, Katrine T; Clausen, Henrik

2018-05-11

The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O -glycan sites. Moreover, we found that O -glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11-mediated O -glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O -glycosylation of LDLR-related proteins and identified conserved O -glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11-mediated LDLR and VLDLR O -glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O -glycosylation increased affinity for LDL by ∼5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Serum amyloid A stimulates macrophage foam cell formation via lectin-like oxidized low-density lipoprotein receptor 1 upregulation

International Nuclear Information System (INIS)

Lee, Ha Young; Kim, Sang Doo; Baek, Suk-Hwan; Choi, Joon Hyuk; Cho, Kyung-Hyun; Zabel, Brian A.; Bae, Yoe-Sik

2013-01-01

Highlights: ► SAA induced macrophage foam cell formation. ► SAA stimulated upregulation of lectin-like oxidized low-density lipoprotein receptor 1 (LOX1). ► SAA-induced LOX1 expression and foam cell formation is mediated by JNK/NF-κB signaling. ► HDL-conjugated SAA also stimulates foam cell formation via LOX1 upregulation. ► The finding reveals a novel mechanism of action of SAA in the pathogenesis of atherosclerosis. -- Abstract: Elevated levels of serum amyloid A (SAA) is a risk factor for cardiovascular diseases, however, the role of SAA in the pathophysiology of atherosclerosis remains unclear. Here we show that SAA induced macrophage foam cell formation. SAA-stimulated foam cell formation was mediated by c-jun N-terminal kinase (JNK) signaling. Moreover, both SAA and SAA-conjugated high density lipoprotein stimulated the expression of the important scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) via nuclear factor-κB (NF-κB). A LOX1 antagonist carrageenan significantly blocked SAA-induced foam cell formation, indicating that SAA promotes foam cell formation via LOX1 expression. Our findings therefore suggest that SAA stimulates foam cell formation via LOX1 induction, and thus likely contributes to atherogenesis

Serum amyloid A stimulates macrophage foam cell formation via lectin-like oxidized low-density lipoprotein receptor 1 upregulation

Energy Technology Data Exchange (ETDEWEB)

Lee, Ha Young, E-mail: hayoung@skku.edu [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Kim, Sang Doo [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Baek, Suk-Hwan [Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Joon Hyuk [Department of Pathology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Cho, Kyung-Hyun [School of Biotechnology, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Zabel, Brian A. [Palo Alto Institute for Research and Education, Veterans Affairs Hospital, Palo Alto, CA 94304 (United States); Bae, Yoe-Sik, E-mail: yoesik@skku.edu [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710 (Korea, Republic of)

2013-03-29

Highlights: ► SAA induced macrophage foam cell formation. ► SAA stimulated upregulation of lectin-like oxidized low-density lipoprotein receptor 1 (LOX1). ► SAA-induced LOX1 expression and foam cell formation is mediated by JNK/NF-κB signaling. ► HDL-conjugated SAA also stimulates foam cell formation via LOX1 upregulation. ► The finding reveals a novel mechanism of action of SAA in the pathogenesis of atherosclerosis. -- Abstract: Elevated levels of serum amyloid A (SAA) is a risk factor for cardiovascular diseases, however, the role of SAA in the pathophysiology of atherosclerosis remains unclear. Here we show that SAA induced macrophage foam cell formation. SAA-stimulated foam cell formation was mediated by c-jun N-terminal kinase (JNK) signaling. Moreover, both SAA and SAA-conjugated high density lipoprotein stimulated the expression of the important scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) via nuclear factor-κB (NF-κB). A LOX1 antagonist carrageenan significantly blocked SAA-induced foam cell formation, indicating that SAA promotes foam cell formation via LOX1 expression. Our findings therefore suggest that SAA stimulates foam cell formation via LOX1 induction, and thus likely contributes to atherogenesis.

Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL)

NARCIS (Netherlands)

Sorrentino, Vincenzo; Scheer, Lilith; Santos, Ana; Reits, Eric; Bleijlevens, Boris; Zelcer, Noam

2011-01-01

We recently identified the liver X receptor-regulated E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL) as a modulator of lipoprotein metabolism. Acting as an E3 ubiquitin ligase, IDOL triggers ubiquitination and subsequent degradation of the low density lipoprotein receptor (LDLR).

Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.

Science.gov (United States)

Zhu, Lin; Giunzioni, Ilaria; Tavori, Hagai; Covarrubias, Roman; Ding, Lei; Zhang, Youmin; Ormseth, Michelle; Major, Amy S; Stafford, John M; Linton, MacRae F; Fazio, Sergio

2016-08-01

Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages. Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression. Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1. © 2016 American Heart Association, Inc.

Rapid characterization of disease-causing mutations in the low density lipoprotein receptor (LDL-R) gene by overexpression in COS cells

DEFF Research Database (Denmark)

Jensen, T G; Andresen, B S; Jensen, H K

1996-01-01

To characterize disease-causing mutations in the low density lipoprotein receptor (LDL-R) gene, COS cells are transfected with the mutant gene in an EBV-based expression vector and characterized by flow cytometry. Using antibodies against the LDL-receptor the amount of receptor protein on the cel...

Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding

International Nuclear Information System (INIS)

Innerarity, T.L.; Weisgraber, K.H.; Arnold, K.S.; Mahley, R.W.; Krauss, R.M.; Vega, G.L.; Grundy, S.M.

1987-01-01

Previous in vivo turnover studies suggested that retarded clearance of low density lipoproteins (LDL) from the plasma of some hypercholesterolemic patients is due to LDL with defective receptor binding. The present study examined this postulate directly by receptor binding experiments. The LDL from a hypercholesterolemic patient (G.R.) displayed a reduced ability to bind to the LDL receptors on normal human fibroblasts. The G.R. LDL possessed 32% of normal receptor binding activity. Likewise, the G.R. LDL were much less effective than normal LDL in competing with 125 I-labeled normal LDL for cellular uptake and degradation and in stimulating intracellular cholesteryl ester synthesis. The defect in LDL binding appears to be due to a genetic abnormality of apolipoprotein B-100: two brothers of the proband possess LDL defective in receptor binding, whereas a third brother and the proband's son have normally binding LDL. Further, the defect in receptor binding does not appear to be associated wit an abnormal lipid composition or structure of the LDL. Normal and abnormal LDL subpopulations were partially separated from plasma of two subjects by density-gradient ultracentrifugation, a finding consistent with the presence of a normal and a mutant allele. The affected family members appear to be heterozygous for this disorder, which has been designated familial defective apolipoprotein B-100. These studies indicate that the defective receptor binding results in inefficient clearance of LDL and the hypercholesterolemia observed in these patients

Low-Density Lipoprotein Receptor–Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction

Directory of Open Access Journals (Sweden)

Stefano Toldo, PhD

2017-10-01

Full Text Available Low-density lipoprotein receptor–related protein-1 (LRP1 is a ubiquitous membrane receptor functioning as a scavenger and regulatory receptor, inducing anti-inflammatory and prosurvival signals. Based on the known structure–activity of the LRP1 receptor binding site, the authors synthesized a small peptide (SP16. SP16 induced a >50% reduction in infarct size (p < 0.001 and preservation of left ventricular systolic function (p < 0.001, and treatment with an LRP1 blocking antibody eliminated the protective effects of SP16. In conclusion, LRP1 activation with SP16 given within 30 min of reperfusion during experimental acute myocardial infarction leads to a cardioprotective signal reducing infarct size and preservation of cardiac systolic function.

Low density lipoproteins mediated nanoplatforms for cancer targeting

International Nuclear Information System (INIS)

Jain, Anupriya; Jain, Keerti; Kesharwani, Prashant; Jain, Narendra K.

2013-01-01

Chemotherapy is a foremost remedial approach for the treatment of localized and metastasized tumors. In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. One such difference may be that of increased receptor-mediated cellular uptake of low density lipoproteins (LDLs) by cancer cells. Lipoproteins in general and specifically LDL are ideal candidates for loading and delivering cancer therapeutic and diagnostic agents due to their biocompatibility. By mimicking the endogenous shape and structure of lipoproteins, the reconstituted lipoproteins can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body’s defenses. In this account, we review the field of low density inspired nanoparticles in relation to the delivery of cancer imaging and therapeutic agents. LDL has instinctive cancer targeting potential and has been used to incorporate various lipophillic molecules to transport them to tumors. Nature’s method of rerouting LDL provides a strategy to extend the cancer targeting potential of lipoproteins far off its constricted purview. In this review, we have discussed the various aspects of LDL including its role in cancer imaging and chemotherapy in retrospect and prospect and current efforts aimed to further improve the delivery efficacy of LDL–drug complexes with reduced chances of drug resistance leading to optimal drug delivery. This review provides a strong support for the concept of using LDL as a drug carrier

Low density lipoproteins mediated nanoplatforms for cancer targeting

Energy Technology Data Exchange (ETDEWEB)

Jain, Anupriya; Jain, Keerti; Kesharwani, Prashant, E-mail: prashant_pharmacy04@rediffmail.com; Jain, Narendra K., E-mail: jnarendr@yahoo.co.in [Dr. H. S. Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India)

2013-09-15

Chemotherapy is a foremost remedial approach for the treatment of localized and metastasized tumors. In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. One such difference may be that of increased receptor-mediated cellular uptake of low density lipoproteins (LDLs) by cancer cells. Lipoproteins in general and specifically LDL are ideal candidates for loading and delivering cancer therapeutic and diagnostic agents due to their biocompatibility. By mimicking the endogenous shape and structure of lipoproteins, the reconstituted lipoproteins can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. In this account, we review the field of low density inspired nanoparticles in relation to the delivery of cancer imaging and therapeutic agents. LDL has instinctive cancer targeting potential and has been used to incorporate various lipophillic molecules to transport them to tumors. Nature's method of rerouting LDL provides a strategy to extend the cancer targeting potential of lipoproteins far off its constricted purview. In this review, we have discussed the various aspects of LDL including its role in cancer imaging and chemotherapy in retrospect and prospect and current efforts aimed to further improve the delivery efficacy of LDL-drug complexes with reduced chances of drug resistance leading to optimal drug delivery. This review provides a strong support for the concept of using LDL as a drug carrier.

Low density lipoproteins mediated nanoplatforms for cancer targeting

Science.gov (United States)

Jain, Anupriya; Jain, Keerti; Kesharwani, Prashant; Jain, Narendra K.

2013-09-01

Chemotherapy is a foremost remedial approach for the treatment of localized and metastasized tumors. In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. One such difference may be that of increased receptor-mediated cellular uptake of low density lipoproteins (LDLs) by cancer cells. Lipoproteins in general and specifically LDL are ideal candidates for loading and delivering cancer therapeutic and diagnostic agents due to their biocompatibility. By mimicking the endogenous shape and structure of lipoproteins, the reconstituted lipoproteins can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. In this account, we review the field of low density inspired nanoparticles in relation to the delivery of cancer imaging and therapeutic agents. LDL has instinctive cancer targeting potential and has been used to incorporate various lipophillic molecules to transport them to tumors. Nature's method of rerouting LDL provides a strategy to extend the cancer targeting potential of lipoproteins far off its constricted purview. In this review, we have discussed the various aspects of LDL including its role in cancer imaging and chemotherapy in retrospect and prospect and current efforts aimed to further improve the delivery efficacy of LDL-drug complexes with reduced chances of drug resistance leading to optimal drug delivery. This review provides a strong support for the concept of using LDL as a drug carrier.

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) in sickle cell disease vasculopathy

Science.gov (United States)

Chen, Mingyi; Qiu, Hong; Lin, Xin; Nam, David; Ogbu-Nwobodo, Lucy; Archibald, Hannah; Joslin, Amelia; Wun, Ted; Sawamura, Tatsuya; Green, Ralph

2017-01-01

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL. Increased expression of LOX-1 has been demonstrated in atherosclerotic lesions and diabetic vasculopathy. In this study, we investigate the expression of LOX-1 receptor in sickle cell disease (SCD) vasculopathy. Expression of LOX-1 in brain vascular endothelium is markedly increased and LOX-1 gene expression is upregulated in cultured human brain microvascular endothelial cells by incubation with SCD erythrocytes. Also, the level of circulating soluble LOX-1 concentration is elevated in the plasma of SCD patients. Increased LOX-1 expression in endothelial cells is potentially involved in the pathogenesis of SCD vasculopathy. Soluble LOX-1 concentration in SCD may provide a novel biomarker for risk stratification of sickle cell vascular complications. PMID:27519944

What are lipoproteins doing in the brain?

Science.gov (United States)

Wang, Hong; Eckel, Robert H

2014-01-01

Lipoproteins in plasma transport lipids between tissues, however, only high-density lipoproteins (HDL) appear to traverse the blood-brain barrier (BBB); thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes, and are found on HDL. In the hippocampus and other brain regions, lipoproteins help to regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, acting through lipoprotein lipase (LPL) and the low-density lipoprotein (LDL) receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting low-density lipoprotein receptors with protein-only nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Xu, Zhikun [Universitat Autònoma de Barcelona, Institut de Biotecnologia i de Biomedicina (Spain); Céspedes, María Virtudes [CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) (Spain); Unzueta, Ugutz [Universitat Autònoma de Barcelona, Institut de Biotecnologia i de Biomedicina (Spain); Álamo, Patricia [CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) (Spain); Pesarrodona, Mireia [Universitat Autònoma de Barcelona, Institut de Biotecnologia i de Biomedicina (Spain); Mangues, Ramón [CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) (Spain); Vázquez, Esther; Villaverde, Antonio, E-mail: antoni.villaverde@uab.cat; Ferrer-Miralles, Neus, E-mail: neus.ferrer@uab.cat [Universitat Autònoma de Barcelona, Institut de Biotecnologia i de Biomedicina (Spain)

2015-03-15

Low-density lipoprotein receptors (LDLR) are appealing cell surface targets in drug delivery, as they are expressed in the blood–brain barrier (BBB) endothelium and are able to mediate transcytosis of functionalized drugs for molecular therapies of the central nervous system (CNS). On the other hand, brain-targeted drug delivery is currently limited, among others, by the poor availability of biocompatible vehicles, as most of the nanoparticles under development as drug carriers pose severe toxicity issues. In this context, protein nanoparticles offer functional versatility, easy and cost-effective bioproduction, and full biocompatibility. In this study, we have designed and characterized several chimerical proteins containing different LDLR ligands, regarding their ability to bind and internalize target cells and to self-organize as viral mimetic nanoparticles of about 18 nm in diameter. While the self-assembling of LDLR-binding proteins as nanoparticles positively influences cell penetration in vitro, the nanoparticulate architecture might be not favoring BBB crossing in vivo. These findings are discussed in the context of the use of nanostructured materials as vehicles for the systemic treatment of CNS diseases.

Targeting low-density lipoprotein receptors with protein-only nanoparticles

International Nuclear Information System (INIS)

Xu, Zhikun; Céspedes, María Virtudes; Unzueta, Ugutz; Álamo, Patricia; Pesarrodona, Mireia; Mangues, Ramón; Vázquez, Esther; Villaverde, Antonio; Ferrer-Miralles, Neus

2015-01-01

Low-density lipoprotein receptors (LDLR) are appealing cell surface targets in drug delivery, as they are expressed in the blood–brain barrier (BBB) endothelium and are able to mediate transcytosis of functionalized drugs for molecular therapies of the central nervous system (CNS). On the other hand, brain-targeted drug delivery is currently limited, among others, by the poor availability of biocompatible vehicles, as most of the nanoparticles under development as drug carriers pose severe toxicity issues. In this context, protein nanoparticles offer functional versatility, easy and cost-effective bioproduction, and full biocompatibility. In this study, we have designed and characterized several chimerical proteins containing different LDLR ligands, regarding their ability to bind and internalize target cells and to self-organize as viral mimetic nanoparticles of about 18 nm in diameter. While the self-assembling of LDLR-binding proteins as nanoparticles positively influences cell penetration in vitro, the nanoparticulate architecture might be not favoring BBB crossing in vivo. These findings are discussed in the context of the use of nanostructured materials as vehicles for the systemic treatment of CNS diseases

Accumulation of native and methylated low density lipoproteins by healing rabbit arterial wall

International Nuclear Information System (INIS)

Fischman, A.J.; Lees, A.M.; Lees, R.S.; Barlai-Kovach, M.; Strauss, H.W.

1987-01-01

To determine whether healing arterial wall accumulation of low density lipoproteins (LDL) is mediated by the high affinity LDL receptor, normocholesterolemic rabbits were injected with 125 I-LDL, /sup 99m/Tc-LDL, or the reductively methylated analogs of these compounds ( 125 I-MeLDL, /sup 99m/Tc-MeLDL), 1 month after balloon catheter deendothelialization of the abdominal aorta. If the mechanism of accumulation requires interaction with the LDL receptor, reductively methylated lipoproteins which do not bind to the receptor should not accumulate in healing arterial wall. Twenty-four hours after injection of labelled lipoproteins, each animal was injected with Evans blue dye, in order to distinguish reendothelialized from deendothelialized aorta. One hour after dye injection, the aorta was fixed, removed, divided into abdominal (ballooned) and thoracic (unballooned) regions and counted. For all lipoprotein preparations, there were three to four times as many counts in the abdominal as in the thoracic aorta. En face autoradiographs were made of the aortas that had been exposed to 125 I-labelled lipoproteins. In the autoradiographs, the areas of the lowest activity corresponded to the centers of healing endothelial islands. The most intense radioactivity for both lipoproteins occurred in the region of the leading edge of the endothelial islands where active endothelial regeneration was in progress. The overall distribution of native and MeLDL accumulation was the same. The results suggest that low density lipoproteins are accumulated in areas of active endothelial regeneration by a mechanism that does not involve the high affinity LDL receptor

Impaired low-density lipoprotein receptor activity in chronic B-lymphocytic leukaemia cells

Energy Technology Data Exchange (ETDEWEB)

Juliusson, G.; Vitols, S.

1988-01-01

Cellular degradation of /sup 125/I-labelled low-density lipoprotein (LDL) was analysed in freshly isolated blood mononuclear cells from 26 patients with chronic B-lymphocytic leukaemia (CLL) and 8 healthy subjects, and in cells following 1,2 and 3 d of culture in medium containing 10% human lipoprotein-deficient serum (LPDS). Fresh CLL cells had lower LDL degradation rates than mononuclear cells from healthy subjects (p < 0.01). The LDL degradation rates increased during culture (p < 0.001), but to a lesser degree in CLL cells than in normal blood mononuclear cells (p < 0.001). The cellular degradation rate of /sup 125/I-LDL was markedly inhibited by an excess of unlabelled LDL, indicating that most of the /sup 125/I-LDL that was degraded had been internalized following binding to the LPDS-induced LDL degradation of CLL cells and the thymidine uptake in CLL cell cultures with (r = 0.70, p < 0.001) and without (r = 0.59, p < 0.01) the B cell mitogen, Epstein-Barr virus. The results indicate that LDL receptors might be involved in the regulation of CLL cell proliferation.

Low density lipoprotein uptake by an endothelial-smooth muscle cell bilayer

International Nuclear Information System (INIS)

Alexander, J.J.; Miguel, R.; Graham, D.

1991-01-01

To study the interaction of endothelial and smooth muscle cells, and the means by which such interaction may affect lipid permeability of the arterial wall, cell bilayers were established by use of a transwell culture system. After confluent growth of both cell types had been achieved, iodine 125 bound to low-density lipoprotein (10 ng protein/ml) was added to the media of the upper well. After a 3-hour incubation period, the iodine 125-bound low-density lipoprotein content of the upper and lower media demonstrated an impedance to lipoprotein movement across the endothelial cell monolayer as compared to the bare porous polycarbonate filter of the transwell (p less than 10(-6)). The presence of smooth muscle cells in the bottom well significantly enhanced the permeability of the endothelial cell layer (p less than 10(-60)). This effect remained unchanged over a 9-day time course. Membrane binding and cellular uptake of low-density lipoprotein by endothelial cells was not altered by smooth muscle cells, indicating that this change in permeability could not be easily attributed to changes in receptor-mediated transport or transcytosis. Membrane binding (p less than 0.02) and cellular uptake (p less than 10(-6)) of low-density lipoprotein by smooth muscle cells in the bilayer, when adjusted for counts available in the smooth muscle cell media, were both reduced in the early incubation period as compared to isolated smooth muscle cells. The disproportionate reduction in uptake as compared to binding would suggest that this was not entirely a receptor-dependent process

Effects of human low and high density lipoproteins on the binding of rat intermediate density lipoproteins to rat liver membranes

International Nuclear Information System (INIS)

Brissette, L.; Nol, S.P.

1986-01-01

Upon incubation with rat liver membranes, radioiodinated rat intermediate density lipoproteins (IDL) interacted with at least two binding sites having a low and a high affinity as demonstrated by the curvilinear Scatchard plots obtained from the specific binding data. The purpose of our work was to identify the nature of these binding sites. Human low density lipoproteins (LDL), contain apolipoprotein B only, and human high density lipoproteins (HDL3), containing neither apolipoprotein B nor E, were both capable of decreasing the specific binding of rat 125 I-IDL. The Scatchard analysis clearly revealed that only the low affinity component was affected by the addition of these human lipoproteins. In fact, the low affinity binding component gradually decreased as the amount of human LDL or HDL3 increased in the binding assay. At a 200-fold excess of human LDL or HDL3, the low affinity binding was totally masked, and the Scatchard plot of the specific 125 I-IDL binding became linear. Only the high affinity binding component was left, enabling a precise measurement of its binding parameters. In a series of competitive displacement experiments in which the binding assay contained a 200-fold excess of human LDL or HDL3, only unlabeled rat IDL effectively displaced the binding of rat 125 I-IDL. We conclude that the low affinity binding of rat IDL to rat liver membranes is due to weak interactions with unspecified lipoprotein binding sites. The camouflage of these sites by human lipoproteins makes possible the study of IDL binding to the high affinity component which likely represents the combined effect of IDL binding to both the remnant and the LDL receptors

Demonstration of functional low-density lipoprotein receptors by protein blotting in fibroblasts from a subject with homozygous receptor-negative familial hypercholesterolemia

International Nuclear Information System (INIS)

Semenkovich, C.F.; Ostlund, R.E. Jr.; Yang, J.; Reaban, M.E.

1985-01-01

We report the detection of low-density lipoprotein (LDL) receptors by the technique of receptor blotting in fibroblasts from a patient with homozygous familial hypercholesterolemia (FHC) previously classified as ''receptor negative.'' Solubilized receptors were electrophoresed, transferred to nitrocellulose paper, treated with LDL followed by radiolabeled antibody to LDL, and visualized by autoradiography. GM 2000 FHC fibroblasts revealed LDL receptors with an apparent molecular weight of approximately 140,000, the same as in normal cells. LDL receptor activity by blotting in GM 2000 cells was greatly diminished in comparison with normal cells, but was calcium dependent. Receptor activity was also detectable by conventional monolayer binding and degradation assays. Thus, GM 2000 cells have profoundly diminished LDL receptor activity, but retain the genetic capacity to make LDL receptor material of normal molecular weight that is capable of binding LDL. Previous studies have demonstrated the presence of trace amounts of immunoreactive LDL receptor protein in fibroblasts from some receptor-negative FHC homozygotes. These studies are extended by demonstrating the ability of this material to bind LDL

Interfacial Tension and Surface Pressure of High Density Lipoprotein, Low Density Lipoprotein, and Related Lipid Droplets

DEFF Research Database (Denmark)

Ollila, O. H. S.; Lamberg, A.; Lehtivaara, M.

2012-01-01

) are essentially lipid droplets surrounded by specific proteins, their main function being to transport cholesterol. Interfacial tension and surface pressure of these particles are of great interest because they are related to the shape and the stability of the droplets and to protein adsorption at the interface....... Here we use coarse-grained molecular-dynamics simulations to consider a number of related issues by calculating the interfacial tension in protein-free lipid droplets, and in HDL and LDL particles mimicking physiological conditions. First, our results suggest that the curvature dependence......Lipid droplets play a central role in energy storage and metabolism on a cellular scale. Their core is comprised of hydrophobic lipids covered by a surface region consisting of amphiphilic lipids and proteins. For example, high and low density lipoproteins (HDL and LDL, respectively...

The low-density lipoprotein receptor-related protein 10 is a negative regulator of the canonical Wnt/β-catenin signaling pathway

International Nuclear Information System (INIS)

Jeong, Young-Hee; Sekiya, Manami; Hirata, Michiko; Ye, Mingjuan; Yamagishi, Azumi; Lee, Sang-Mi; Kang, Man-Jong; Hosoda, Akemi; Fukumura, Tomoe; Kim, Dong-Ho; Saeki, Shigeru

2010-01-01

Wnt signaling pathways play fundamental roles in the differentiation, proliferation and functions of many cells as well as developmental, growth, and homeostatic processes in animals. Low-density lipoprotein receptor (LDLR)-related protein (LRP) 5 and LRP6 serve as coreceptors of Wnt proteins together with Frizzled receptors, triggering activation of canonical Wnt/β-catenin signaling. Here, we found that LRP10, a new member of the LDLR gene family, inhibits the canonical Wnt/β-catenin signaling pathway. The β-catenin/T cell factor (TCF) transcriptional activity in HEK293 cells was activated by transfection with Wnt3a or LRP6, which was then inhibited by co-transfection with LRP10. Deletion of the extracellular domain of LRP10 negated its inhibitory effect. The inhibitory effect of LRP10 was consistently conserved in HEK293 cells even when GSK3β phosphorylation was inhibited by incubation with lithium chloride and co-transfection with constitutively active S33Y-mutated β-catenin. Nuclear β-catenin accumulation was unaffected by LRP10. The present studies suggest that LRP10 may interfere with the formation of the β-catenin/TCF complex and/or its binding to target DNA in the nucleus, and that the extracellular domain of LRP10 is critical for inhibition of the canonical Wnt/β-catenin signaling pathway.

Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice

DEFF Research Database (Denmark)

Christoffersen, Christina; Jauhiainen, Matti; Moser, Markus

2008-01-01

To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM(-/-)) mice. Plasma apoM was predominantly associated with 10-12-nm alpha-migrating HDL particles. Human apoM overexpression (11-fol...

Germinated Brown Rice Attenuates Atherosclerosis and Vascular Inflammation in Low-Density Lipoprotein Receptor-Knockout Mice.

Science.gov (United States)

Zhao, Ruozhi; Ghazzawi, Nora; Wu, Jiansu; Le, Khuong; Li, Chunyang; Moghadasian, Mohammed H; Siow, Yaw L; Apea-Bah, Franklin B; Beta, Trust; Yin, Zhengfeng; Shen, Garry X

2018-05-02

The present study investigates the impact of germinated brown rice (GBR) on atherosclerosis and the underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The intensity of atherosclerosis in aortas of LDLr-KO mice receiving diet supplemented with 60% GBR (weight/weight) was significantly less than that in mice fed with 60% white rice (WR) or control diet ( p mice fed with WR diet was significantly more than that from mice receiving the control diet ( p mice in comparison to the WR diet ( p mice compared to WR. The anti-atherosclerotic effect of GBR in LDLr-KO mice at least in part results from its anti-inflammatory activity.

Cellular uptake of lipoproteins and persistent organic compounds-An update and new data

International Nuclear Information System (INIS)

Hjelmborg, Philip Sebastian; Andreassen, Thomas Kjaergaard; Bonefeld-Jorgensen, Eva Cecilie

2008-01-01

There are a number of interactions related to the transport of lipophilic xenobiotic compounds in the blood stream of mammals. This paper will focus on the interactions between lipoproteins and persistent organic pollutants (POPs) and how these particles are taken up by cells. A number of POPs including the pesticide p,p'-dichlorodiphenyltrichloroethane (DDT), and especially its metabolite p,p'-dichlorodiphenyldichloroethene (DDE), interacts with nuclear hormone receptors causing these to malfunction, which in turn results in a range of deleterious health effects in humans. The aim of the present study was to determine the role of lipoprotein receptors in mouse embryonic fibroblast (MEF) cells in conjunction with uptake of DDT-lipoprotein complexes from supplemented media in vitro. Uptake of DDT by MEF cells was investigated using MEF1 cells carrying the receptors low-density lipoprotein receptor-related protein (LRP) and low-density lipoprotein receptor (LDLR) present and MEF4 cells with no LRP and LDLR expression. Cells were incubated together with the complex of low-density lipoproteins (LDL) and [ 14 C]DDT. The receptor function was further evaluated by adding the 40 kDa receptor-associated protein (RAP) which blocks receptor activity. The results showed that [ 14 C]DDT uptake was decreasing when the LDL concentration was increasing. There was no strong evidence for a receptor-mediated uptake of the [ 14 C]DDT-lipoprotein complex. To conclude, DDT travels in the blood stream and can cross cell membranes while being transported as a DDT-lipoprotein complex. The lipoproteins do not need receptors to cross cell membranes since passive diffusion constitutes a major passageway

Association of polymorphisms in low-density lipoprotein receptor- related protein 5 gene with bone mineral density in postmenopausal Chinese women

Institute of Scientific and Technical Information of China (English)

Zhen-lin ZHANG; Yue-juan QIN; Jin-wei HE; Qi-ren HUANG; Miao LI; Yun-qiu HU; Yu-juan LIU

2005-01-01

Aim: To investigate the possible association of Q89R, N740N and A1330V polymorphisms in low-density lipoprotein receptor-related protein 5 (LRP5) gene with bone mineral density (BMD) in postmenopausal Chinese women. Methods: Q89R,N740N and A1330V genotypes were determined by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) in 647 unrelated healthy postmenopausal Han Chinese women aged 43-76 years in Shanghai. BMD at lumbar spine 1-4 and the left proximal femur including the femoral neck, trochanter and Ward's triangle were measured by dual-energy X-ray absorptionmetry in all subjects. Results: The distribution of the Q89R, N740N and A1330V genotypes in this population was as follows: QQ 80.5%, QR 18.7%, and RR 0.8%; TT 66.9%,TC 31.1%, and CC 2.0%; AA 68.0%, AV 29.7%, and VV 2.3%. The frequencies of the Q89R, N740N and A1330V genotypes and alleles did not deviate from the HardyWeinberg equilibrium. We found that the Q89R and A1330V polymorphisms were in linkage disequilibrium in our population (x2= 13.50, P＜0.01). Both before and after adjusting for age, years since menopause, height, and weight, the Q89R or N740N genotypes were significantly associated with BMD at the femoral neck (P＜0.05).Subjects with the Q89R QQ genotype or the N740N TT genotype had a significantly higher BMD at the femoral neck, compared with those with the QR/RR or TC/CC genotypes, respectively. No significant association was found between A1330V polymorphism and BMD at any site. Conclusion: Our findings suggest that the LRP5 gene is a candidate for the genetic determination of BMD in postmenopausal Chinese women.

Liver lipase and high-density lipoprotein. Lipoprotein changes after incubation of human serum with rat liver lipase.

Science.gov (United States)

Groot, P H; Scheek, L M; Jansen, H

1983-05-16

Human sera were incubated with rat liver lipase after inactivation of lecithin:cholesterol acyltransferase, and the changes in serum lipoprotein composition were measured. In the presence of liver lipase serum triacylglycerol and phosphatidylcholine were hydrolyzed. The main changes in the concentrations of these lipids were found in the high-density lipoprotein fraction. Subfractionation of high-density lipoprotein by rate-zonal ultracentrifugation showed a prominent decrease in all constituents of high-density lipoprotein2, a smaller decrease in the 'light' high-density lipoprotein3 and an increase in the 'heavy' high-density lipoprotein3. These data support a concept in which liver lipase is involved in high-density lipoprotein2 phospholipid and triacylglycerol catabolism and suggest that as a result of this action high-density lipoprotein2 is converted into high-density lipoprotein3.

Electronegative Low-Density Lipoprotein Increases C-Reactive Protein Expression in Vascular Endothelial Cells through the LOX-1 Receptor

OpenAIRE

Chu, Chih-Sheng; Wang, Yu-Chen; Lu, Long-Sheng; Walton, Brian; Yilmaz, H. Ramazan; Huang, Roger Y.; Sawamura, Tatsuya; Dixon, Richard A. F.; Lai, Wen-Ter; Chen, Chu-Huang; Lu, Jonathan

2013-01-01

Objectives Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1. Methods and Results Plasma LDL sa...

Acetaldehyde binding increases the catabolism of rat serum low-density lipoproteins

International Nuclear Information System (INIS)

Savolainen, M.J.; Baraona, E.; Lieber, C.S.

1987-01-01

Acetaldehyde was found to form adducts with rat serum lipoproteins. The binding of [ 14 C]acetaldehyde to lipoproteins was studied at low concentrations which are known to exist during ethanol oxidation. The amount of lipoprotein adducts was a linear function of acetaldehyde concentration up to 250 μM. Incubation of rat plasma low-density lipoproteins (LDL) with 200 μM acetaldehyde increased the disappearance rate of the 3 H-label from the cholesterol ester moiety of LDL injected into normal rats. The data show that even low concentrations of acetaldehyde are capable of affecting LDL metabolism. These findings may provide an explanation for the low concentrations of serum LDL in alcoholics. The alcohol-induced hyperlipidemia includes either a lack of increase or a decrease in the low-density lipoprotein (LDL) concentration, but the underlying mechanism is not known. It has been shown previously, that the acetylation of lysine residues of LDL apoprotein (apoB) by acetanhydride leads to rapid uptake of LDL particles by macrophages through a non-LDL receptor pathway. Since acetaldehyde, the first toxic metabolite of ethanol, is a chemically reactive compound capable of binding to proteins, they tested whether acetaldehyde forms adducts with serum lipoproteins and subsequently alters the catabolism of LDL. 19 references, 2 figures, 1 table

Hemodynamics alter arterial low-density lipoprotein metabolism

International Nuclear Information System (INIS)

Warty, V.S.; Calvo, W.J.; Berceli, S.A.; Pham, S.M.; Durham, S.J.; Tanksale, S.K.; Klein, E.C.; Herman, I.M.; Borovetz, H.S.

1989-01-01

We have investigated the role of hemodynamic factors on low-density lipoprotein transport and metabolism in the intact arterial wall. Freshly excised canine carotid blood vessels were exposed to well-defined pulsatile flow in vitro for continuous periods up to 20 hours. We chose to impose the following hemodynamic conditions on our test carotid arteries: normotension, hypertension (at physiologic flow conditions), and hypertension coupled with elevated flow of canine serum perfusate. In several experiments the effect of endothelial denudation was examined in carotid arteries exposed to normotensive pulsatile flow. A trapped ligand method was used for quantitating low-density lipoprotein uptake and metabolism in the arterial wall. The distribution of both intact and degraded low-density lipoprotein fractions was determined from measurements of radiolabelled low-density lipoprotein activity within thin radial sections of perfused arteries. Our results suggest that both hypertensive hemodynamic simulations exacerbate the uptake of low-density lipoprotein within the arterial wall (by a factor of three to nine). The percentage of low-density lipoprotein that undergoes irreversible degradation falls from 41% under normotensive conditions to below 30% when hypertensive conditions are imposed, indicating that degradative processes are not proportionally elevated with the accelerated influx. A similar pattern is observed for deendothelialized vessels

Triglycerides, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol in rats exposed to premium motor spirit fumes.

Science.gov (United States)

Aberare, Ogbevire L; Okuonghae, Patrick; Mukoro, Nathaniel; Dirisu, John O; Osazuwa, Favour; Odigie, Elvis; Omoregie, Richard

2011-06-01

Deliberate and regular exposure to premium motor spirit fumes is common and could be a risk factor for liver disease in those who are occupationally exposed. A possible association between premium motor spirit fumes and plasma levels of triglyceride, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol using a rodent model could provide new insights in the pathology of diseases where cellular dysfunction is an established risk factor. The aim of this study was to evaluate the possible effect of premium motor spirit fumes on lipids and lipoproteins in workers occupationally exposed to premium motor spirit fumes using rodent model. Twenty-five Wister albino rats (of both sexes) were used for this study between the 4(th) of August and 7(th) of September, 2010. The rats were divided into five groups of five rats each. Group 1 rats were not exposed to premium motor spirit fumes (control group), group 2 rats were exposed for 1 hour daily, group 3 for 3 hours daily, group 4 for 5 hours daily and group 5 for 7 hours daily. The experiment lasted for a period of 4 weeks. Blood samples obtained from all the groups after 4 weeks of exposure were used for the estimation of plasma levels of triglyceride, total cholesterol, high density lipoprotein- cholesterol and low density lipoprotein- cholesterol. Results showed significant increase in means of plasma total cholesterol and low density lipoprotein levels (P<0.05). The mean triglyceride and total body weight were significantly lower (P<0.05) in the exposed group when compared with the unexposed. The plasma level of high density lipoprotein, the ratio of low density lipoprotein to high density lipoprotein and the ratio of total cholesterol to high density lipoprotein did not differ significantly in exposed subjects when compared with the control group. These results showed that frequent exposure to petrol fumes may be highly deleterious to the liver cells.

In vivo regulation of scavenger receptor BI and the selective uptake of high density lipoprotein cholesteryl esters in rat liver parenchymal and Kupffer cells

NARCIS (Netherlands)

Fluiter, K.; van der Westhuijzen, D. R.; van Berkel, T. J.

1998-01-01

High density lipoprotein cholesteryl esters (HDL-CE) are selectively taken up by liver parenchymal cells without parallel apolipoprotein uptake. This selective uptake route forms an important step in the so-called reverse cholesterol transport. Scavenger receptor BI (SR-BI) is the only known HDL

Activated platelets contribute to oxidized low-density lipoproteins and dysfunctional high-density lipoproteins through a phospholipase A2-dependent mechanism

NARCIS (Netherlands)

Blache, Denis; Gautier, Thomas; Tietge, Uwe J. F.; Lagrost, Laurent

Plasma activity of secretory phospholipase A2 (sPLA2) increases in patients with cardiovascular disease. The present study investigated whether platelet-released sPLA2 induces low-density lipoprotein (LDL) and high-density lipoprotein (HDL) modifications that translate into changes in lipoprotein

Radiochemical and immunohistochemical detection of low density lipoprotein surface binding by lymphocytes

International Nuclear Information System (INIS)

Melzner, I.; Hambitzer, R.; Haferkamp, O.

1983-01-01

Human peripheral blood lymphocytes bind and take up low density lipoprotein (LDL) by receptor-mediated endocytosis. The binding of LDL was determiend by incubation with 125 I-LDL and an immunohistochemical assay. By both techniques a diminished rate of binding was found when cells were freshly isolated from the blood, but increased 5 to 10 fold when lymphocytes were incubated in lipoprotein-deficient medium for 72 hours. In addition, it was shown immunohistochemically that only few ceels showed an LDL-dependent fluorescent labelling: approximately 5 to 10 % of the freshly isolated lymphocytes and 40 to 50 % of the cells incubated for 72 hours under lipoprotein-free conditions. The present data indicate that not only the high affinity LDL receptor described by Goldstein and Braun may be involved in the uptake of cholesterol by lymphocytes, but also other binding sites, which may have immunological function in some lymphocyte subpopulations. (author)

Cellular uptake of lipoproteins and Persistent Organic Compounds - An update and new data

DEFF Research Database (Denmark)

Hjelmborg, Philip Sebastian; Andreassen, Thomas Kjærgaard; Bonefeld-Jørgensen, Eva Cecilie

2008-01-01

including the pesticide DDT (p,p'-dichlorodiphenyltrichloroethane), and especially its metabolite DDE (p,p'-dichlorodiphenyldichloroethene), interacts with nuclear hormone receptors causing these to malfunction, which in turn results in a range of deleterious health effects in humans. The aim of the present...... study was to determine the role of lipoprotein receptors in mouse embryonic fibroblast (MEF) cells in conjunction with uptake of DDT-lipoprotein complexes from supplemented media in vitro. Uptake of DDT by MEF cells was investigated using MEF1 cells carrying the receptors LRP (low-density lipoprotein...... receptor-related protein) and LDLR (low density lipoprotein receptor) present and MEF4 cells with no LRP and LDLR expression. Cells were incubated together with the complex of LDL and [14C]DDT. The receptor function was further evaluated by adding the 40 kDa receptor-associated protein (RAP) which blocks...

Metabolism of lipoproteins by human fetal hepatocytes

International Nuclear Information System (INIS)

Carr, B.R.

1987-01-01

The rate of clearance of lipoproteins from plasma appears to play a role in the development of atherogenesis. The liver may account for as much as two thirds of the removal of low-density lipoprotein and one third of the clearance of high-density lipoprotein in certain animal species and humans, mainly by receptor-mediated pathways. The purpose of the present investigation was to determine if human fetal hepatocytes maintained in vitro take up and degrade lipoproteins. We first determined that the maximal binding capacity of iodine 125-iodo-LDL was approximately 300 ng of low-density lipoprotein protein/mg of membrane protein and an apparent dissociation constant of approximately 60 micrograms low-density lipoprotein protein/ml in membranes prepared from human fetal liver. We found that the maximal uptake of [ 125 I]iodo-LDL and [ 125 I]iodo-HDL by fetal hepatocytes occurred after 12 hours of incubation. Low-density lipoprotein uptake preceded the appearance of degradation products by 4 hours, and thereafter the degradation of low-density lipoprotein increased linearly for at least 24 hours. In contrast, high-density lipoprotein was not degraded to any extent by fetal hepatocytes. [ 125 I]Iodo-LDL uptake and degradation were inhibited more than 75% by preincubation with low-density lipoprotein but not significantly by high-density lipoprotein, whereas [ 125 I]iodo-HDL uptake was inhibited 70% by preincubation with high-density lipoprotein but not by low-density lipoprotein. In summary, human fetal hepatocytes take up and degrade low-density lipoprotein by a receptor-mediated process similar to that described for human extrahepatic tissues

Analysis of a two-domain binding site for the urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex in low-density-lipoprotein-receptor-related protein.

Science.gov (United States)

Andersen, O M; Petersen, H H; Jacobsen, C; Moestrup, S K; Etzerodt, M; Andreasen, P A; Thøgersen, H C

2001-07-01

The low-density-lipoprotein-receptor (LDLR)-related protein (LRP) is composed of several classes of domains, including complement-type repeats (CR), which occur in clusters that contain binding sites for a multitude of different ligands. Each approximately 40-residue CR domain contains three conserved disulphide linkages and an octahedral Ca(2+) cage. LRP is a scavenging receptor for ligands from extracellular fluids, e.g. alpha(2)-macroglobulin (alpha(2)M)-proteinase complexes, lipoprotein-containing particles and serine proteinase-inhibitor complexes, like the complex between urokinase-type plasminogen activator (uPA) and the plasminogen activator inhibitor-1 (PAI-1). In the present study we analysed the interaction of the uPA-PAI-1 complex with an ensemble of fragments representing a complete overlapping set of two-domain fragments accounting for the ligand-binding cluster II (CR3-CR10) of LRP. By ligand blotting, solid-state competition analysis and surface-plasmon-resonance analysis, we demonstrate binding to multiple CR domains, but show a preferential interaction between the uPA-PAI-1 complex and a two-domain fragment comprising CR domains 5 and 6 of LRP. We demonstrate that surface-exposed aspartic acid and tryptophan residues at identical positions in the two homologous domains, CR5 and CR6 (Asp(958,CR5), Asp(999,CR6), Trp(953,CR5) and Trp(994,CR6)), are critical for the binding of the complex as well as for the binding of the receptor-associated protein (RAP) - the folding chaperone/escort protein required for transport of LRP to the cell surface. Accordingly, the present work provides (1) an identification of a preferred binding site within LRP CR cluster II; (2) evidence that the uPA-PAI-1 binding site involves residues from two adjacent protein domains; and (3) direct evidence identifying specific residues as important for the binding of uPA-PAI-1 as well as for the binding of RAP.

Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy

OpenAIRE

Zabirnyk, Olga; Liu, Wei; Khalil, Shadi; Sharma, Anit; Phang, James M.

2009-01-01

Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible ...

α-Tocopherol modulates the low density lipoprotein receptor of human HepG2 cells

Directory of Open Access Journals (Sweden)

Bottema Cynthia DK

2003-05-01

Full Text Available Abstract The aim of this study was to determine the effects of vitamin E (α-tocopherol on the low density lipoprotein (LDL receptor, a cell surface protein which plays an important role in controlling blood cholesterol. Human HepG2 hepatoma cells were incubated for 24 hours with increasing amounts of α, δ, or γ-tocopherol. The LDL receptor binding activity, protein and mRNA, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase mRNA, cell cholesterol and cell lathosterol were measured. The effect of α-tocopherol was biphasic. Up to a concentration of 50 μM, α-tocopherol progressively increased LDL receptor binding activity, protein and mRNA to maximum levels 2, 4 and 6-fold higher than control, respectively. The HMG-CoA reductase mRNA and the cell lathosterol concentration, indices of cholesterol synthesis, were also increased by 40% over control by treatment with 50 μM α-tocopherol. The cell cholesterol concentration was decreased by 20% compared to control at 50 μM α-tocopherol. However, at α-tocopherol concentrations higher than 50 μM, the LDL receptor binding activity, protein and mRNA, the HMG-CoA reductase mRNA and the cell lathosterol and cholesterol concentrations all returned to control levels. The biphasic effect on the LDL receptor was specific for α-tocopherol in that δ and γ-tocopherol suppressed LDL receptor binding activity, protein and mRNA at all concentrations tested despite the cells incorporating similar amounts of the three homologues. In conclusion, α-tocopherol, exhibits a specific, concentration-dependent and biphasic "up then down" effect on the LDL receptor of HepG2 cells which appears to be at the level of gene transcription. Cholesterol synthesis appears to be similarly affected and the cell cholesterol concentration may mediate these effects.

Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism

DEFF Research Database (Denmark)

Steiner, Carine; Holleboom, Adriaan G; Karuna, Ratna

2012-01-01

BA (bile acid) formation is considered an important final step in RCT (reverse cholesterol transport). HDL (high-density lipoprotein) has been reported to transport BAs. We therefore investigated the effects of monogenic disturbances in human HDL metabolism on serum concentrations and lipoprotein...... concentrations of conjugated and secondary BAs differed between heterozygous carriers of SCARB1 (scavenger receptor class B1) mutations and unaffected individuals (P...

Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations.

Science.gov (United States)

Dubé, Joseph B; Wang, Jian; Cao, Henian; McIntyre, Adam D; Johansen, Christopher T; Hopkins, Scarlett E; Stringer, Randa; Hosseinzadeh, Siyavash; Kennedy, Brooke A; Ban, Matthew R; Young, T Kue; Connelly, Philip W; Dewailly, Eric; Bjerregaard, Peter; Boyer, Bert B; Hegele, Robert A

2015-02-01

Inuit are considered to be vulnerable to cardiovascular disease because their lifestyles are becoming more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified 2 nonsynonymous variants in low-density lipoprotein receptor (LDLR), namely p.G116S and p.R730W. Genotyping these variants in 3324 Inuit from Alaska, Canada, and Greenland showed they were common, with allele frequencies 10% to 15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P=5.6×10(-49)), which was >3× larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 2.34-3.90; P=1.7×10(-17)), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand-binding activity compared with wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol level nor altered in vitro activity. LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications. © 2014 American Heart Association, Inc.

Receptor-mediated endocytosis and intracellular trafficking of insulin and low-density lipoprotein by retinal vascular endothelial cells.

Science.gov (United States)

Stitt, A W; Anderson, H R; Gardiner, T A; Bailie, J R; Archer, D B

1994-08-01

The authors investigated the receptor-mediated endocytosis (RME) and intracellular trafficking of insulin and low-density lipoprotein (LDL) in cultured retinal vascular endothelial cells (RVECs). Low-density lipoprotein and insulin were conjugated to 10 nm colloidal gold, and these ligands were added to cultured bovine RVECs for 20 minutes at 4 degrees C. The cultures were then warmed to 37 degrees C and fixed after incubation times between 30 seconds and 1 hour. Control cells were incubated with unconjugated gold colloid at times and concentrations similar to those of the ligands. Additional control cells were exposed to several concentrations of anti-insulin receptor antibody or a saturating solution of unconjugated insulin before incubation with gold insulin. Using transmission electron microscopy, insulin gold and LDL gold were both observed at various stages of RME. Insulin-gold particles were first seen to bind to the apical plasma membrane (PM) before clustering in clathrin-coated pits and internalization in coated vesicles. Gold was later visualized in uncoated cytoplasmic vesicles, corresponding to early endosomes and multivesicular bodies (MVBs) or late endosomes. In several instances, localized regions of the limiting membrane of the MVBs appeared coated, a feature of endosomal membranes not previously described. After RME at the apical PM and passage through the endosomal system, the greater part of both insulin- and LDL-gold conjugates was seen to accumulate in large lysosome-like compartments. However, a small but significant proportion of the internalized ligands was transcytosed and released as discrete membrane-associated quanta at the basal cell surface. The uptake of LDL gold was greatly increased in highly vacuolated, late-passage RVECs. In controls, anti-insulin receptor antibody and excess unconjugated insulin caused up to 89% inhibition in gold-insulin binding and internalization. These results illustrate the internalization and intracellular

Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease

DEFF Research Database (Denmark)

Wittrup, Hans H; Andersen, Rolf V; Tybjaerg-Hansen, Anne

2006-01-01

Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD).......Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD)....

Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme

Energy Technology Data Exchange (ETDEWEB)

Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.

2006-06-14

This paper discribes a synthetic low density lipoprotein(LDL) made by complexing a 29 amino acid that consists of a lipid bindingdomain and the LDL receptor binding domain with a lipid microemulsion.The nano-LDL particles were intermdiate in size between LDL and HDL andbound to LDL receptors on GBM brain tumor cells. Synthetic nano-LDLuptake by GBM cells was LDL receptor specific and dependent on cellreceptor number. It is suggested that these synthetic particles can serveas a delivery vehicle for hydophobic anti-tumor drugs by targeting theLDL receptor.

Polymorphisms of the low-density lipoprotein receptor gene in Brazilian individuals with heterozygous familial hypercholesterolemia

Directory of Open Access Journals (Sweden)

L.A. Salazar

2000-11-01

Full Text Available Familial hypercholesterolemia (FH is a metabolic disorder inherited as an autosomal dominant trait characterized by an increased plasma low-density lipoprotein (LDL level. The disease is caused by several different mutations in the LDL receptor gene. Although early identification of individuals carrying the defective gene could be useful in reducing the risk of atherosclerosis and myocardial infarction, the techniques available for determining the number of the functional LDL receptor molecules are difficult to carry out and expensive. Polymorphisms associated with this gene may be used for unequivocal diagnosis of FH in several populations. The aim of our study was to evaluate the genotype distribution and relative allele frequencies of three polymorphisms of the LDL receptor gene, HincII1773 (exon 12, AvaII (exon 13 and PvuII (intron 15, in 50 unrelated Brazilian individuals with a diagnosis of heterozygous FH and in 130 normolipidemic controls. Genomic DNA was extracted from blood leukocytes by a modified salting-out method. The polymorphisms were detected by PCR-RFLP. The FH subjects showed a higher frequency of A+A+ (AvaII, H+H+ (HincII1773 and P1P1 (PvuII homozygous genotypes when compared to the control group (P<0.05. In addition, FH probands presented a high frequency of A+ (0.58, H+ (0.61 and P1 (0.78 alleles when compared to normolipidemic individuals (0.45, 0.45 and 0.64, respectively. The strong association observed between these alleles and FH suggests that AvaII, HincII1773 and PvuII polymorphisms could be useful to monitor the inheritance of FH in Brazilian families.

Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells

Energy Technology Data Exchange (ETDEWEB)

McNutt, Markey C.; Kwon, Hyock Joo; Chen, Chiyuan; Chen, Justin R.; Horton, Jay D.; Lagace, Thomas A.; (USMC); (UTSMC)

2009-07-10

PCSK9 is a secreted protein that degrades low density lipoprotein receptors (LDLRs) in liver by binding to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. It is not known whether PCSK9 causes degradation of LDLRs within the secretory pathway or following secretion and reuptake via endocytosis. Here we show that a mutation in the LDLR EGF-A domain associated with familial hypercholesterolemia, H306Y, results in increased sensitivity to exogenous PCSK9-mediated cellular degradation because of enhanced PCSK9 binding affinity. The crystal structure of the PCSK9-EGF-A(H306Y) complex shows that Tyr-306 forms a hydrogen bond with Asp-374 in PCSK9 at neutral pH, which strengthens the interaction with PCSK9. To block secreted PCSK9 activity, LDLR (H306Y) subfragments were added to the medium of HepG2 cells stably overexpressing wild-type PCSK9 or gain-of-function PCSK9 mutants associated with hypercholesterolemia (D374Y or S127R). These subfragments blocked secreted PCSK9 binding to cell surface LDLRs and resulted in the recovery of LDLR levels to those of control cells. We conclude that PCSK9 acts primarily as a secreted factor to cause LDLR degradation. These studies support the concept that pharmacological inhibition of the PCSK9-LDLR interaction extracellularly will increase hepatic LDLR expression and lower plasma low density lipoprotein levels.

Metabolism of cholesteryl esters of rat very low density lipoproteins.

Science.gov (United States)

Faergeman, O; Havel, R J

1975-06-01

Rat very low density lipoproteins (d smaller than 1.006), biologically labeled in esterified and free cholesterol, were obtained form serum 6 h after intravenous injection of particulate (3-H) cholesterol. When injected into recipient animals, the esterified cholesterol was cleared form plasma with a half-life of 5 min. After 15 min, 71% of the injected esterified (3-H) cholesterol had been taken up by the liver, where it was rapidly hydrolyzed. After 60 min only 3.3% of the amount injected had been transferred, via lipoproteins of intermediate density, to the low density lipoproteins of plasma (d 1.019-1.063). Both uptake in the liver and transfer to low density lipoproteins occurred without change of distribution of 3-H in the various cholesteryl esters. 3-H appearing in esterified cholesterol of high density lipoproteins (d greater than 1.063) was derived from esterification, presumably by lecithin: cholesterol acyltransferase, of simultaneously injected free (3-H) cholesterol. Content of free (3-H) cholesterol in the very low density lipoproteins used for injection could be reduced substantially by incubation with erythrocytes. This procedure, however, increased the rate of clearance of the lipoproteins after injection into recipient rats. These studies show that hepatic removal is the major catabolic pathway for cholesteryl esters of rat very low density lipoproteins and that transfer to low density lipoproteins occurs to only a minor extent.

Lectin-like oxidized low-density lipoprotein receptor-1 promotes endothelial dysfunction in LDL receptor knockout background.

Science.gov (United States)

Hofmann, Anja; Brunssen, Coy; Poitz, David M; Langbein, Heike; Strasser, Ruth H; Henle, Thomas; Ravens, Ursula; Morawietz, Henning

2017-11-01

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date. Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr -/- ) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph. WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr -/- mice (Eff max : 56.7 ± 23.0%) compared to WT (Eff max : 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Eff max : 76.7 ± 12.9%, P < 0.05) and Ldlr -/- mice (Eff max : 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr -/- mice were detectable when comparing all genotypes. Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Activated α2 -Macroglobulin Induces Mesenchymal Cellular Migration Of Raw264.7 Cells Through Low-Density Lipoprotein Receptor-Related Protein 1.

Science.gov (United States)

Ferrer, Darío G; Dato, Virginia Actis; Fincati, Javier R Jaldín; Lorenc, Valeria E; Sánchez, María C; Chiabrando, Gustavo A

2017-07-01

Distinct modes of cell migration contribute to diverse types of cell movements. The mesenchymal mode is characterized by a multistep cycle of membrane protrusion, the formation of focal adhesion, and the stabilization at the leading edge associated with the degradation of extracellular matrix (ECM) components and with regulated extracellular proteolysis. Both α 2 -Macroglobulin (α 2 M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), play important roles in inflammatory processes, by controlling the extracellular activity of several proteases. The binding of the active form of α 2 M (α 2 M*) to LRP1 can also activate different signaling pathways in macrophages, thus inducing extracellular matrix metalloproteinase-9 (MMP-9) activation and cellular proliferation. In the present study, we investigated whether the α 2 M*/LRP1 interaction induces cellular migration of the macrophage-derived cell line, Raw264.7. By using the wound-scratch migration assay and confocal microscopy, we demonstrate that α 2 M* induces LRP1-mediated mesenchymal cellular migration. This migration exhibits the production of enlarged cellular protrusions, MT1-MMP distribution to these leading edge protrusions, actin polymerization, focal adhesion formation, and increased intracellular LRP1/β1-integrin colocalization. Moreover, the presence of calphostin-C blocked the α 2 M*-stimulated cellular protrusions, suggesting that the PKC activation is involved in the cellular motility of Raw264.7 cells. These findings could constitute a therapeutic target for inflammatory processes with deleterious consequences for human health, such as rheumatoid arthritis, atherosclerosis and cancer. J. Cell. Biochem. 118: 1810-1818, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effect of phospholipase A treatment of low density lipoproteins on the dextran sulfate--lipoprotein interaction.

Science.gov (United States)

Nishida, T

1968-09-01

The effect of phospholipase A on the interaction of low density lipoproteins of the S(f) 0-10 class with dextran sulfate was studied in phosphate buffer of pH 7.4, ionic strength 0.1, by chemical, spectrophotometric, and centrifugal methods. When low density lipoproteins that had been treated with phospholipase A were substituted for untreated lipoproteins, the amount of insoluble dextran sulfate-lipoprotein complex formed was greatly reduced. Hydrolysis of over 20% of the lecithin and phosphatidyl ethanolamine constituents of the lipoproteins prevented the formation of insoluble complex. However, even the lipoproteins in which almost all the phosphoglycerides were hydrolyzed produced soluble complex, which was converted to insoluble complex upon addition of magnesium sulfate. It is apparent that the lipoproteins altered extensively by treatment with phospholipase A retain many characteristic properties of native low density lipoproteins. Fatty acids, but not lysolecithin, released by the action of phospholipase A interfered with the formation of insoluble complex; this interference was due to association of the fatty acids with the lipoproteins. With increases in the concentration of the associated fatty acids, the amounts of magnesium ion required for the conversion of soluble complex to insoluble complex increased progressively. Charge interaction is evidently of paramount importance in the formation of sulfated polysaccharide-lipoprotein complexes.

A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein

DEFF Research Database (Denmark)

Whorton, Matthew R; Bokoch, Michael P; Rasmussen, Søren Gøgsig Faarup

2007-01-01

G protein-coupled receptors (GPCRs) respond to a diverse array of ligands, mediating cellular responses to hormones and neurotransmitters, as well as the senses of smell and taste. The structures of the GPCR rhodopsin and several G proteins have been determined by x-ray crystallography, yet...... the organization of the signaling complex between GPCRs and G proteins is poorly understood. The observations that some GPCRs are obligate heterodimers, and that many GPCRs form both homo- and heterodimers, has led to speculation that GPCR dimers may be required for efficient activation of G proteins. However......, technical limitations have precluded a definitive analysis of G protein coupling to monomeric GPCRs in a biochemically defined and membrane-bound system. Here we demonstrate that a prototypical GPCR, the beta2-adrenergic receptor (beta2AR), can be incorporated into a reconstituted high-density lipoprotein...

Identification of the Oxidized Low-Density Lipoprotein Scavenger Receptor CD36 in Plasma

DEFF Research Database (Denmark)

Handberg, Aase; Levin, Klaus; Højlund, Kurt

2006-01-01

BACKGROUND: Macrophage CD36 scavenges oxidized low-density lipoprotein, leading to foam cell formation, and appears to be a key proatherogenic molecule. Increased expression of CD36 has been attributed to hyperglycemia and to defective macrophage insulin signaling in insulin resistance. Premature...

Oxidized low-density lipoprotein in postmenopausal women

DEFF Research Database (Denmark)

Jankowski, Vera; Just, Alexander R; Pfeilschifter, Johannes

2014-01-01

BACKGROUND: Oxidized low-density lipoprotein (oxLDL) leads to atherosclerosis and cardiovascular disease, the most frequent causes of death worldwide. After menopause, lipid and lipoprotein metabolism changes and women are at greater risk of cardiovascular disease compared to fertile women. The aim.......10-0.43). Although intima-media thickness did not differ, postmenopausal women with serous oxLDL had more often atherosclerotic plaques compared to women without oxLDL (6/66 vs. 0/467; P lipoprotein, impaired glucose intolerance, and DBP were independently associated...... with the occurrence of oxLDL. If oxLDL was present, higher high-density lipoprotein and glucose intolerance were associated with higher concentrations of oxLDL. In contrast, higher blood urea concentrations were associated with lower concentrations of oxLDL. CONCLUSION: This study presents the prevalence...

Genetic spectrum of low density lipoprotein receptor gene variations in South Indian population.

Science.gov (United States)

ArulJothi, K N; Suruthi Abirami, B; Devi, Arikketh

2018-03-01

Low density lipoprotein receptor (LDLR) is a membrane bound receptor maintaining cholesterol homeostasis along with Apolipoprotein B (APOB), Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and other genes of lipid metabolism. Any pathogenic variation in these genes alters the function of the receptor and leads to Familial Hypercholesterolemia (FH) and other cardiovascular diseases. This study was aimed at screening the LDLR, APOB and PCSK9 genes in Hypercholesterolemic patients to define the genetic spectrum of FH in Indian population. Familial Hypercholesterolemia patients (n=78) of South Indian Tamil population with LDL cholesterol and Total cholesterol levels above 4.9mmol/l and 7.5mmol/l with family history of Myocardial infarction were involved. DNA was isolated by organic extraction method from blood samples and LDLR, APOB and PCSK9 gene exons were amplified using primers that cover exon-intron boundaries. The amplicons were screened using High Resolution Melt (HRM) Analysis and the screened samples were sequenced after purification. This study reports 20 variations in South Indian population for the first time. In this set of variations 9 are novel variations which are reported for the first time, 11 were reported in other studies also. The in silico analysis for all the variations detected in this study were done to predict the probabilistic effect in pathogenicity of FH. This study adds 9 novel variations and 11 recurrent variations to the spectrum of LDLR gene mutations in Indian population. All these variations are reported for the first time in Indian population. This spectrum of variations was different from the variations of previous Indian reports. Copyright © 2017 Elsevier B.V. All rights reserved.

Hypervariable region 1 deletion and required adaptive envelope mutations confer decreased dependency on scavenger receptor class B type I and low-density lipoprotein receptor for hepatitis C virus

DEFF Research Database (Denmark)

Prentoe, Jannick; Serre, Stéphanie B N; Ramirez, Santseharay

2014-01-01

-deleted viruses. Apolipoprotein E (ApoE)-specific HCV neutralization was similar for H77, J6, and S52 viruses with and without HVR1. In conclusion, HVR1 and HVR1-related adaptive envelope mutations appeared to be involved in LDLr and SR-BI dependency, respectively. Also, LDLr served Apo....../S733F), S52(ΔHVR1/A369V), and S52(A369V), but not for J6(ΔHVR1). Low-density lipoprotein receptor (LDLr) dependency was decreased for HVR1-deleted viruses, but not for H77(N476D/S733F) and S52(A369V). Soluble LDLr neutralization revealed strong inhibition of parental HCV but limited effect against HVR1...

Comparative reactivity of the myeloperoxidase-derived oxidants HOCl and HOSCN with low-density lipoprotein (LDL)

DEFF Research Database (Denmark)

Ismael, Fahd O; Proudfoot, Julie M; Brown, Bronwyn E

2015-01-01

Atherosclerosis is characterised by the accumulation of lipids within macrophages in the artery wall. Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces ox...

The Influence of Decreased Levels of High Density Lipoprotein ...

African Journals Online (AJOL)

very low density lipoprotein cholesterol, and triglyceride were assayed. ... Abiodun and Gwarzo: Association of high density lipoprotein cholesterol with haemolysis in sickle cell disease ... analyses were carried out to determine the correlation.

High-density lipoproteins inhibit urate crystal-induced inflammation in mice

OpenAIRE

Scanu Anna; Luisetto Roberto; Oliviero Francesca; Gruaz Lyssia; Sfriso Paolo; Burger Danielle; Punzi Leonardo

2015-01-01

Objectives To investigate the effects and mechanisms of action of high density lipoproteins (HDL) in monosodium urate (MSU) crystal induced inflammation—that is gouty inflammation in vivo. Methods Air pouches raised on the backs of mice were injected with MSU crystals or tumour necrosis factor (TNF) in the presence or absence of HDL and/or interleukin (IL) 1 receptor antagonist (IL 1Ra) for 3 h. Leucocyte count and neutrophil percentage in pouch fluids were measured using a haemocytometer an...

Low-density lipoprotein analysis in microchip capillary electrophoresis systems

NARCIS (Netherlands)

Ceriotti, Laura; Shibata, Takayuki; Folmer, Britta; Weiller, Bruce H.; Roberts, Matthew A.; De Rooij, Nico F.; Verpoorte, Elisabeth

2002-01-01

Due to the mounting evidence for altered lipoprotein and cholesterol-lipoprotein content in several disease states, there has been an increasing interest in analytical methods for lipoprotein profiling for diagnosis. The separation of low- and high-density lipoproteins (LDL and HDL, respectively)

On-treatment non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipid ratios in relation to residual vascular risk after treatment with potent statin therapy

DEFF Research Database (Denmark)

Mora, Samia; Glynn, Robert J; Boekholdt, S Matthijs

2012-01-01

The goal of this study was to determine whether residual risk after high-dose statin therapy for primary prevention individuals with reduced levels of low-density lipoprotein cholesterol (LDL-C) is related to on-treatment apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), tri...

Comparative studies of vertebrate scavenger receptor class B type 1: a high-density lipoprotein binding protein

Directory of Open Access Journals (Sweden)

Holmes RS

2012-06-01

Full Text Available Roger S Holmes,1,2 Laura A Cox11Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA; 2School of Biomolecular and Physical Sciences, Griffith University, Nathan, Queensland, AustraliaAbstract: Scavenger receptor class B type 1 protein (SCARB1 plays an essential role in cholesterol homeostasis and functions in binding high density lipoprotein cholesterol (HDL in liver and other tissues of the body. SCARB1 also functions in lymphocyte homeostasis and in the uptake of hepatitis C virus (HCV by the liver. A genetic deficiency of this protein results in autoimmune disorders and significant changes in blood cholesterol phenotype. Comparative SCARB1 amino acid sequences and structures and SCARB1 gene locations were examined using data from several vertebrate genome projects. Vertebrate SCARB1 sequences shared 50%–99% identity as compared with 28%–31% sequence identities with other CD36-like superfamily members, ie, SCARB2 and SCARB3 (also called CD36. At least eight N-glycosylation sites were conserved among most of the vertebrate SCARB1 proteins examined. Sequence alignments, key amino acid residues, and conserved predicted secondary structures were also studied, including: cytoplasmic, transmembrane, and exoplasmic sequences; conserved N-terminal and C-terminal transmembrane glycines which participate in oligomer formation; conserved cystine disulfides and a free SH residue which participates in lipid transport; carboxyl terminal PDZ-binding domain sequences (Ala507-Arg/Lys508-Leu509; and 30 conserved proline and 18 conserved glycine residues, which may contribute to short loop formation within the exoplasmic HDL-binding sequence. Vertebrate SCARB1 genes usually contained 12 coding exons. The human SCARB1 gene contained CpG islands, micro RNA binding sites, and several transcription factor binding sites (including PPARG which may contribute to the high level (13.7 times

Effect of high density lipoproteins on permeability of rabbit aorta to low density lipoproteins

International Nuclear Information System (INIS)

Klimov, A.N.; Popov, V.A.; Nagornev, V.A.; Pleskov, V.M.

1985-01-01

A study was made on the effect of high density lipoproteins (HDL) on the permeability of rabbit aorta to low density lipoproteins (LDL) after intravenous administration of human HDL and human ( 125 I)LDL to normal and hypercholesterolemic rabbits. Evaluation of radioactivity in plasma and aorta has shown that the administration of a large dose of HDL decreased the aorta permeability rate for ( 125 I)LDL on an average by 19% in normal rabbits, and by 45% in rabbits with moderate hypercholesterolemia. A historadiographic study showed that HDL also decreased the vessel wall permeability to ( 125 I)LDL in normal and particularly in hypercholesterolemic animals. The suggestion was made that HDL at very high molar concentration can hamper LDL transportation through the intact endothelial layer into the intima due to the ability of HDL to compete with LDL in sites of low affinity on the surface of endothelial cells. (author)

Existence of B/E and E receptors on Hep-G2 cells: a study using colloidal gold- and 125I-labeled lipoproteins

International Nuclear Information System (INIS)

Hesz, A.; Ingolic, E.; Krempler, F.; Kostner, G.M.

1987-01-01

The presence of specific receptors for apolipoprotein B (low-density lipoproteins) and apolipoprotein E (HDL-E) on Hep-G2 cells and human skin fibroblasts was studied by chemical methods and by electron microscopy using a differential gold labeling technique. Fibroblasts bound both types of lipoproteins to one and the same receptor (B/E receptor) as deduced from competition experiments with HDL-E and LDL. Labeled HDL-E, on the other hand, was only partially displaced by cold LDL but was completely displaced by unlabeled HDL-E. Scatchard analysis of lipoprotein binding to Hep-G2 cells revealed an approx 10 times higher binding affinity of apoE-containing lipoproteins as compared to apoB-containing ones. No differences between apoE- or apoB-containing lipoproteins with respect to the morphology of cell binding and intracellular processing were observed. The results are compatible with the concept that Hep-G2 cells possess two kinds of receptors, one specific for apoB- and apoE-containing lipoproteins (B/E receptor) and another specific for apoE only. From these studies we conclude that Hep-G2 cells may serve as a suitable model for studying the lipoprotein metabolism in the liver

Cholesterol transfer from normal and atherogenic low density lipoproteins to Mycoplasma membranes

International Nuclear Information System (INIS)

Mitschelen, J.J.; St Clair, R.W.; Hester, S.H.

1981-01-01

The purpose of this study was to determine whether the free cholesterol of hypercholesterolemic low density lipoprotein from cholesterol-fed nonhuman primates has a greater potential for surface transfer to cell membranes than does the free cholesterol of normal low density lipoprotein. The low density lipoproteins were isolated from normal and hypercholesterolemic rhesus and cynomolgus monkeys, incubated with membranes from Acholeplasma laidlawii, a mycoplasma species devoid of cholesterol in its membranes, and the mass transfer of free cholesterol determined by measuring membrane cholesterol content. Since these membranes neither synthesize nor esterify cholesterol, nor degrade the protein or cholesterol ester moieties of low density lipoprotein, they are an ideal model with which to study differences in the cholesterol transfer potential of low density lipoprotein independent of the uptake of the intact low density lipoprotein particle. These studies indicate that, even though there are marked differences in the cholesterol composition of normal and hypercholesterolemic low density lipoproteins, this does not result in a greater chemical potential for surface transfer of free cholesterol. Consequently, if a difference in the surface transfer of free cholesterol is responsible for the enhanced ability of hypercholesterolemic low density lipoprotein to promote cellular cholesterol accumulation and, perhaps, also atherosclerosis, it must be the result of differences in the interaction to the hypercholesterolemic low density lipoprotein with the more complicated mammalian cell membranes, rather than differences in the chemical potential for cholesterol transfer

Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability

NARCIS (Netherlands)

Bredie, S. J.; de Bruin, T. W.; Demacker, P. N.; Kastelein, J. J.; Stalenhoef, A. F.

1995-01-01

We evaluated in a double-blind, placebo-controlled, randomized trial of 45 well-defined patients with familial combined hyperlipidemia, the effect of gemfibrozil (1,200 mg/day) or simvastatin (20 mg/day) on apolipoprotein-B (apo-B)-containing lipoproteins, low-density lipoprotein (LDL) subfraction

Native High Density Lipoproteins (HDL Interfere with Platelet Activation Induced by Oxidized Low Density Lipoproteins (OxLDL

Directory of Open Access Journals (Sweden)

Ivo Volf

2013-05-01

Full Text Available Platelets and lipoproteins play a crucial role in atherogenesis, in part by their ability to modulate inflammation and oxidative stress. While oxidized low density lipoproteins (OxLDL play a central role in the development of this disease, high density lipoproteins (HDL represent an atheroprotective factor of utmost importance. As platelet function is remarkably sensitive to the influence of plasma lipoproteins, it was the aim of this study to clarify if HDL are able to counteract the stimulating effects of OxLDL with special emphasis on aspects of platelet function that are relevant to inflammation. Therefore, HDL were tested for their ability to interfere with pro-thrombotic and pro-inflammatory aspects of platelet function. We are able to show that HDL significantly impaired OxLDL-induced platelet aggregation and adhesion. In gel-filtered platelets, HDL decreased both the formation of reactive oxygen species and CD40L expression. Furthermore, HDL strongly interfered with OxLDL-induced formation of platelet-neutrophil aggregates in whole blood, suggesting that platelets represent a relevant and sensitive target for HDL. The finding that HDL effectively competed with the binding of OxLDL to the platelet surface might contribute to their atheroprotective and antithrombotic properties.

Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene

DEFF Research Database (Denmark)

Fairoozy, Roaa Hani; Cooper, Jackie; White, Jon

2017-01-01

Background and aims: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulat...

Lipoprotein Lipase and PPAR Alpha Gene Polymorphisms, Increased Very-Low-Density Lipoprotein Levels, and Decreased High-Density Lipoprotein Levels as Risk Markers for the Development of Visceral Leishmaniasis by Leishmania infantum

Directory of Open Access Journals (Sweden)

Márcia Dias Teixeira Carvalho

2014-01-01

Full Text Available In visceral leishmaniasis (VL endemic areas, a minority of infected individuals progress to disease since most of them develop protective immunity. Therefore, we investigated the risk markers of VL within nonimmune sector. Analyzing infected symptomatic and, asymptomatic, and noninfected individuals, VL patients presented with reduced high-density lipoprotein cholesterol (HDL-C, elevated triacylglycerol (TAG, and elevated very-low-density lipoprotein cholesterol (VLDL-C levels. A polymorphism analysis of the lipoprotein lipase (LPL gene using HindIII restriction digestion (N = 156 samples (H+ = the presence and H− = the absence of mutation revealed an increased adjusted odds ratio (OR of VL versus noninfected individuals when the H+/H+ was compared with the H−/H− genotype (OR = 21.3; 95% CI = 2.32–3335.3; P = 0.003. The H+/H+ genotype and the H+ allele were associated with elevated VLDL-C and TAG levels (P < 0.05 and reduced HDL-C levels (P < 0.05. An analysis of the L162V polymorphism in the peroxisome proliferator-activated receptor alpha (PPARα gene (n = 248 revealed an increased adjusted OR when the Leu/Val was compared with the Leu/Leu genotype (OR = 8.77; 95% CI = 1.41–78.70; P = 0.014. High TAG (P = 0.021 and VLDL-C (P = 0.023 levels were associated with susceptibility to VL, whereas low HDL (P = 0.006 levels with resistance to infection. The mutated LPL and the PPARα Leu/Val genotypes may be considered risk markers for the development of VL.

Flow-cytometric determination of high-density-lipoprotein binding sites on human leukocytes

International Nuclear Information System (INIS)

Schmitz, G.; Wulf, G.; Bruening, T.A.; Assmann, G.

1987-01-01

In this method, leukocytes were isolated from 6 mL of EDTA-blood by density-gradient centrifugation and subsequently incubated with rhodamine isothiocyanate (RITC)-conjugated high-density lipoproteins (HDL). The receptor-bound conjugate particles were determined by fluorescent flow cytometry and compared with 125 I-labeled HDL binding data for the same cells. Human granulocytes express the highest number of HDL binding sites (9.4 x 10(4)/cell), followed by monocytes (7.3 x 10(4)/cell) and lymphocytes (4.0 x 10(4)/cell). Compared with conventional analysis of binding of 125 I-labeled HDL in tissue-culture dishes, the present determination revealed significantly lower values for nonspecific binding. In competition studies, the conjugate competes for the same binding sites as 125 I-labeled HDL. With the use of tetranitromethane-treated HDL3, which fails to compete for the HDL receptor sites while nonspecific binding is not affected, we could clearly distinguish between 37 degrees C surface binding and specific 37 degrees C uptake of RITC-HDL3, confirming that the HDL receptor leads bound HDL particles into an intracellular pathway rather than acting as a docking type of receptor. Patients with familial dysbetalipoproteinemia showed a significantly higher number of HDL binding sites in the granulocyte population but normal in lymphocytes and monocytes, indicating increased uptake of cholesterol-containing lipoproteins. In patients with familial hypercholesterolemia, HDL binding was increased in all three cell types, indicating increased cholesterol uptake and increased cholesterol synthesis. The present method allows rapid determination of HDL binding sites in leukocytes from patients with various forms of hyper- and dyslipoproteinemias

Caenorhabditis elegans reveals a FxNPxY-independent low-density lipoprotein receptor internalization mechanism mediated by epsin1

Science.gov (United States)

Kang, Yuan-Lin; Yochem, John; Bell, Leslie; Sorensen, Erika B.; Chen, Lihsia; Conner, Sean D.

2013-01-01

Low-density lipoprotein receptor (LDLR) internalization clears cholesterol-laden LDL particles from circulation in humans. Defects in clathrin-dependent LDLR endocytosis promote elevated serum cholesterol levels and can lead to atherosclerosis. However, our understanding of the mechanisms that control LDLR uptake remains incomplete. To identify factors critical to LDLR uptake, we pursued a genome-wide RNA interference screen using Caenorhabditis elegans LRP-1/megalin as a model for LDLR transport. In doing so, we discovered an unanticipated requirement for the clathrin-binding endocytic adaptor epsin1 in LDLR endocytosis. Epsin1 depletion reduced LDLR internalization rates in mammalian cells, similar to the reduction observed following clathrin depletion. Genetic and biochemical analyses of epsin in C. elegans and mammalian cells uncovered a requirement for the ubiquitin-interaction motif (UIM) as critical for receptor transport. As the epsin UIM promotes the internalization of some ubiquitinated receptors, we predicted LDLR ubiquitination as necessary for endocytosis. However, engineered ubiquitination-impaired LDLR mutants showed modest internalization defects that were further enhanced with epsin1 depletion, demonstrating epsin1-mediated LDLR endocytosis is independent of receptor ubiquitination. Finally, we provide evidence that epsin1-mediated LDLR uptake occurs independently of either of the two documented internalization motifs (FxNPxY or HIC) encoded within the LDLR cytoplasmic tail, indicating an additional internalization mechanism for LDLR. PMID:23242996

Selective uptake of a toxic lipophilic anthracycline derivative by the low-density lipoprotein receptor pathway in cultured fibroblasts

International Nuclear Information System (INIS)

Vitols, S.G.; Masquelier, M.; Peterson, C.O.

1985-01-01

N-(N-Retinoyl)-L-leucyldoxorubicin 14-linoleate (r11-DOX), a new lipophilic derivative of doxorubicin, was synthesized and incorporated into low-density lipoprotein (LDL). The drug-LDL complex contained 100- 200 drug molecules/LDL particle. When cultured normal human fibroblasts were incubated with 125 I-LDL-incorporated drug, there was a perfect correlation between the cellular uptake plus degradation of 125 I-LDL and the cellular drug accumulation. The presence of excess native LDL inhibited the cellular uptake and degradation of 125 I-LDL and the drug accumulation to the same extent. In contrast, methylated LDL, which does not bind to the LDL receptor, did not alter the cellular uptake and degradation of 125 I-LDL nor did it alter the drug accumulation. When LDL receptor negative fibroblasts from a patient with the homozygous form of familial hypercholesterolemia were incubated with the drug- 125 I-LDL complex, cellular drug accumulation was very low. The drug-LDL complex inhibited the growth of cultured normal human fibroblasts. The drug incorporated into methylated LDL was much less toxic. These findings suggest that r11-DOX incorporated into LDL is delivered to cells selectively by the LDL receptor pathway. This might be of value in the treatment of leukemia, since it has been previously found that leukemic cells exhibit higher LDL receptor activity than white blood cells and bone marrow cells from healthy subjects

Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice.

Directory of Open Access Journals (Sweden)

Florian Willecke

Full Text Available We tested whether a high fat diet (HFD containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/- mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR. After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD, showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ-treated hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states.

Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease

DEFF Research Database (Denmark)

Lundegaard, Christiane; Tybjærg-Hansen, Anne; Grande, Peer

2010-01-01

Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD).......Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD)....

Macular xanthophylls, lipoprotein-related genes, and age-related macular degeneration.

Science.gov (United States)

Koo, Euna; Neuringer, Martha; SanGiovanni, John Paul

2014-07-01

Plant-based macular xanthophylls (MXs; lutein and zeaxanthin) and the lutein metabolite meso-zeaxanthin are the major constituents of macular pigment, a compound concentrated in retinal areas that are responsible for fine-feature visual sensation. There is an unmet need to examine the genetics of factors influencing regulatory mechanisms and metabolic fates of these 3 MXs because they are linked to processes implicated in the pathogenesis of age-related macular degeneration (AMD). In this work we provide an overview of evidence supporting a molecular basis for AMD-MX associations as they may relate to DNA sequence variation in AMD- and lipoprotein-related genes. We recognize a number of emerging research opportunities, barriers, knowledge gaps, and tools offering promise for meaningful investigation and inference in the field. Overviews on AMD- and high-density lipoprotein (HDL)-related genes encoding receptors, transporters, and enzymes affecting or affected by MXs are followed with information on localization of products from these genes to retinal cell types manifesting AMD-related pathophysiology. Evidence on the relation of each gene or gene product with retinal MX response to nutrient intake is discussed. This information is followed by a review of results from mechanistic studies testing gene-disease relations. We then present findings on relations of AMD with DNA sequence variants in MX-associated genes. Our conclusion is that AMD-associated DNA variants that influence the actions and metabolic fates of HDL system constituents should be examined further for concomitant influence on MX absorption, retinal tissue responses to MX intake, and the capacity to modify MX-associated factors and processes implicated in AMD pathogenesis. © 2014 American Society for Nutrition.

Novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit

International Nuclear Information System (INIS)

Naruszewicz, M.; Carew, T.E.; Pittman, R.C.; Witztum, J.L.; Steinberg, D.

1984-01-01

Treatment of low density lipoprotein (LDL) receptor-deficient rabbits (WHHL rabbits) with probucol (1% w/w in a chow diet) lowered their LDL-cholesterol levels by 36%, consonant with the reported effectiveness of the drug in patients deficient in the LDL receptor. Initial studies of LDL fractional catabolic rate (FCR) using 125 I-labeled LDL prepared from the serum of untreated WHHL rabbits showed no difference between probucol-treated WHHL rabbits and untreated WHHL rabbits. When, however, 125 I-labeled LDL was prepared from donor WHHL rabbits under treatment with probucol and injected back into them, the FCR was found to be increased by about 50% above that measured simultaneously using 131 I-labeled LDL prepared from untreated WHHL donors. The labeled LDL from probucol-treated donors was also metabolized more rapidly than that from untreated donors when injected into untreated WHHL rabbits or into untreated wild-type New Zealand White rabbits. Finally, it was shown that rabbit skin fibroblasts in culture degraded labeled LDL prepared from probucol-treated WHHL rabbits more rapidly than that prepared from untreated WHHL donors. This was true both for normal rabbit fibroblasts and also for WHHL skin fibroblasts, although the absolute degradation rates in the latter were, of course, much lower for both forms of LDL. The data indicate that a major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL of the probucol-treated animal

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

NARCIS (Netherlands)

Dijk, K.W. van; Vlijmen, B.J.M. van; Hof, H.B. van 't; Zee, A. van der; Santamarina-Fojo, S.; Berkel, T.J.C. van; Havekes, L.M.; Hofker, M.H.

1999-01-01

To investigate the quantitative requirement for apolipoprotein (apo) E in the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes

The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling

Directory of Open Access Journals (Sweden)

Dianaly T. Au

2017-01-01

Full Text Available The metabolic syndrome is an escalating worldwide public health concern. Defined by a combination of physiological, metabolic, and biochemical factors, the metabolic syndrome is used as a clinical guideline to identify individuals with a higher risk for type 2 diabetes and cardiovascular disease. Although risk factors for type 2 diabetes and cardiovascular disease have been known for decades, the molecular mechanisms involved in the pathophysiology of these diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1 is a large endocytic and signaling receptor that is widely expressed in several tissues. As a member of the LDL receptor family, LRP1 is involved in the clearance of chylomicron remnants from the circulation and has been demonstrated to be atheroprotective. Recently, studies have shown that LRP1 is involved in insulin receptor trafficking and regulation and glucose metabolism. This review summarizes the role of tissue-specific LRP1 in insulin signaling and its potential role as a link between lipoprotein and glucose metabolism in diabetes.

Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins.

Science.gov (United States)

Gillard, Baiba K; Rosales, Corina; Xu, Bingqing; Gotto, Antonio M; Pownall, Henry J

2018-04-12

Human plasma high-density lipoprotein cholesterol concentrations are a negative risk factor for atherosclerosis-linked cardiovascular disease. Pharmacological attempts to reduce atherosclerotic cardiovascular disease by increasing plasma high-density lipoprotein cholesterol have been disappointing so that recent research has shifted from HDL quantity to HDL quality, that is, functional vs dysfunctional HDL. HDL has varying degrees of dysfunction reflected in impaired reverse cholesterol transport (RCT). In the context of atheroprotection, RCT occurs by 2 mechanisms: one is the well-known trans-hepatic pathway comprising macrophage free cholesterol (FC) efflux, which produces early forms of FC-rich nascent HDL (nHDL). Lecithin:cholesterol acyltransferase converts HDL-FC to HDL-cholesteryl ester while converting nHDL from a disc to a mature spherical HDL, which transfers its cholesteryl ester to the hepatic HDL receptor, scavenger receptor B1 for uptake, conversion to bile salts, or transfer to the intestine for excretion. Although widely cited, current evidence suggests that this is a minor pathway and that most HDL-FC and nHDL-FC rapidly transfer directly to the liver independent of lecithin:cholesterol acyltransferase activity. A small fraction of plasma HDL-FC enters the trans-intestinal efflux pathway comprising direct FC transfer to the intestine. SR-B1 -/- mice, which have impaired trans-hepatic FC transport, are characterized by high plasma levels of a dysfunctional FC-rich HDL that increases plasma FC bioavailability in a way that produces whole-body hypercholesterolemia and multiple pathologies. The design of future therapeutic strategies to improve RCT will have to be formulated in the context of these dual RCT mechanisms and the role of FC bioavailability. Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Current guidelines for high-density lipoprotein cholesterol in therapy and future directions

Directory of Open Access Journals (Sweden)

Subedi BH

2014-04-01

Full Text Available Bishnu H Subedi,1,2 Parag H Joshi,1 Steven R Jones,1 Seth S Martin,1 Michael J Blaha,1 Erin D Michos1 1Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, 2Greater Baltimore Medical Center, Baltimore, MD, USA Abstract: Many studies have suggested that a significant risk factor for atherosclerotic cardiovascular disease (ASCVD is low high-density lipoprotein cholesterol (HDL-C. Therefore, increasing HDL-C with therapeutic agents has been considered an attractive strategy. In the prestatin era, fibrates and niacin monotherapy, which cause modest increases in HDL-C, reduced ASCVD events. Since their introduction, statins have become the cornerstone of lipoprotein therapy, the benefits of which are primarily attributed to decrease in low-density lipoprotein cholesterol. Findings from several randomized trials involving niacin or cholesteryl ester transfer protein inhibitors have challenged the concept that a quantitative elevation of plasma HDL-C will uniformly translate into ASCVD benefits. Consequently, the HDL, or more correctly, HDL-C hypothesis has become more controversial. There are no clear guidelines thus far for targeting HDL-C or HDL due to lack of solid outcomes data for HDL specific therapies. HDL-C levels are only one marker of HDL out of its several structural or functional properties. Novel approaches are ongoing in developing and assessing agents that closely mimic the structure of natural HDL or replicate its various functions, for example, reverse cholesterol transport, vasodilation, anti-inflammation, or inhibition of platelet aggregation. Potential new approaches like HDL infusions, delipidated HDL, liver X receptor agonists, Apo A-I upregulators, Apo A mimetics, and gene therapy are in early phase trials. This review will outline current therapies and describe future directions for HDL therapeutics. Keywords: high-density lipoprotein, lipids, cholesterol, atherosclerosis, cardiovascular disease, therapy

A bovine papillomavirus-1 based vector restores the function of the low-density lipoprotein receptor in the receptor-deficient CHO-ldlA7 cell line

Directory of Open Access Journals (Sweden)

Ustav Mart

2002-04-01

Full Text Available Abstract Background The rationale of using bovine papillomavirus-1 (BPV-1 derived vectors in gene therapy protocols lies in their episomal maintenance at intermediate to high copy number, and stable, high-level expression of the gene products. We constructed the BPV-1 based vector harbouring the human low-density lipoprotein receptor (LDLR gene cDNA and tested its ability to restore the function of the LDLR in the receptor-deficient cell line CHO-ldlA7. Results The introduced vector p3.7LDL produced functionally active LDL receptors in the receptor-deficient cell line CHO-ldlA7 during the 32-week period of observation as determined by the internalisation assay with the labelled LDL particles. Conclusion Bovine papillomavirus type-1 (BPV-1-derived vectors could be suitable for gene therapy due to their episomal maintenance at intermediate to high copy number and stable, high-level expression of the gene products. The constructed BPV-1 based vector p3.7LDL produced functionally active LDL receptors in the LDLR-deficient cell line CHO-ldlA7 during the 32-week period of observation. In vivo experiments should reveal, whether 1–5% transfection efficiency obtained in the current work is sufficient to bring about detectable and clinically significant lowering of the amount of circulating LDL cholesterol particles.

Deletion in the first cysteine-rich repeat of low density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia

International Nuclear Information System (INIS)

Leitersdorf, E.; Hobbs, H.H.; Fourie, A.M.; Jacobs, M.; Van Der Westhuyzen, D.R.; Coetzee, G.A.

1988-01-01

The ligand-binding domain of the low density lipoprotein (LDL) receptor is composed of seven cysteine-rich repeats, each ∼ 40 amino acids long. Previous studies showed that if the first repeat of the ligand-binding domain (encoded by exon 2) is deleted, the receptor fails to bind an anti-LDL receptor monoclonal antibody (IgG-C7) but continues to bind LDL with high affinity. Cultured fibroblasts from a Black South African Xhosa patient (TT) with the clinical syndrome of homozygous familial hypercholesterolemia demonstrated high-affinity cell-surface binding of 125 I-labeled LDL but not 125 I-labeled IgG-C7. previous haplotype analysis, using 10 restriction fragment length polymorphic sites, suggested that the patient inherited two identical LDL receptor alleles. The polymerase chain reaction technique was used to selectively amplify exon 2 of the LDL receptor gene from this patient. Sequence analysis of the amplified fragment disclosed a deletion of six base pairs that removes two amino acids, aspartic acid and glycine, from the first cysteine-rich ligand binding repeat. The mutation creates a new Pst I restriction site that can be used to detect the deletion. The existence of this mutant allele confirms that the epitope of IgG-C7 is located in the first cysteine-rich repeat and that this repeat is not necessary for LDL binding. The mutant gene produced a normally sized 120-kilodalton LDL receptor precursor protein that matured to the 160-kilodalton form at less than one-fourth the normal rate

PCSK9 and triglyceride-rich lipoprotein metabolism.

Science.gov (United States)

Druce, I; Abujrad, H; Ooi, T C

2015-07-20

Pro-protein convertase subtilisin-kexin 9 (PCSK9) is known to affect low-density lipoprotein (LDL) metabolism, but there are indications from several lines of research that it may also influence the metabolism of other lipoproteins, especially triglyceride-rich lipoproteins (TRL). This review summarizes the current data on this possible role of PCSK9. A link between PCSK9 and TRL has been suggested through the demonstration of (1) a correlation between plasma PCSK9 and triglyceride (TG) levels in health and disease, (2) a correlation between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism, (3) an effect of TG-lowering fibrate therapy on plasma PCSK9 levels, (4) an effect of PCSK9 on postprandial lipemia, (5) an effect of PCSK9 on adipose tissue biology, (6) an effect of PCSK9 on apolipoprotein B production from the liver and intestines, (7) an effect of PCSK9 on receptors other than low density lipoprotein receptor (LDLR) that are involved in TRL metabolism, and (8) an effect of anti-PCSK9 therapy on serum TG levels. The underlying mechanisms are unclear but starting to emerge. © 2015 the Journal of Biomedical Research. All rights reserved.

[Residual risk: The roles of triglycerides and high density lipoproteins].

Science.gov (United States)

Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

2016-06-01

In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. © Georg Thieme Verlag KG Stuttgart · New York.

Kaempferol stimulates gene expression of low-density lipoprotein receptor through activation of Sp1 in cultured hepatocytes

Science.gov (United States)

Ochiai, Ayasa; Miyata, Shingo; Iwase, Masamori; Shimizu, Makoto; Inoue, Jun; Sato, Ryuichiro

2016-01-01

A high level of plasma low-density lipoprotein (LDL) cholesterol is considered a risk factor for atherosclerosis. Because the hepatic LDL receptor (LDLR) is essential for clearing plasma LDL cholesterol, activation of LDLR is a promising therapeutic target for patients with atherosclerotic disease. Here we demonstrated how the flavonoid kaempferol stimulated the gene expression and activity of LDLR in HepG2 cells. The kaempferol-mediated stimulation of LDLR gene expression was completely inhibited by knockdown of Sp1 gene expression. Treatment of HepG2 cells with kaempferol stimulated the recruitment of Sp1 to the promoter region of the LDLR gene, as well as the phosphorylation of Sp1 on Thr-453 and Thr-739. Moreover, these kaempferol-mediated processes were inhibited in the presence of U0126, an ERK pathway inhibitor. These results suggest that kaempferol may increase the activity of Sp1 through stimulation of Sp1 phosphorylation by ERK1/2 and subsequent induction of LDLR expression and activity. PMID:27109240

Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.

Science.gov (United States)

Yang, Wei-Na; Ma, Kai-Ge; Qian, Yi-Hua; Zhang, Jian-Shui; Feng, Gai-Feng; Shi, Li-Li; Zhang, Zhi-Chao; Liu, Zhao-Hui

2015-07-01

Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aβ). Reuptake of extracellular Aβ is believed to contribute significantly to the intraneuronal Aβ pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aβ1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aβ internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aβ1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aβ internalization in neurons. We found that extracellular Aβ1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aβ1-42 and LRP1 were also found co-localized in neurons during Aβ1-42 internalization, and they could form Aβ1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aβ1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aβ1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aβ1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aβ levels and served a potential therapeutic target for AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interrelationships between postprandial lipoprotein B:CIII particle changes and high-density lipoprotein subpopulation profiles in mixed hyperlipoproteinemia.

Science.gov (United States)

Saïdi, Y; Sich, D; Camproux, A; Egloff, M; Federspiel, M C; Gautier, V; Raisonnier, A; Turpin, G; Beucler, I

1999-01-01

We studied the relationships postprandially between triglyceride-rich lipoprotein (TRL) and high-density lipoprotein (HDL) in 11 mixed hyperlipoproteinemia (MHL) and 11 hypercholesterolemia (HCL) patients. The high and prolonged postprandial triglyceridemia response observed in MHL but not HCL patients was essentially dependent on very-low-density lipoprotein (VLDL) changes. This abnormal response was related to decreased lipoprotein lipase (LPL) activity (-48.7%, P<.01) in MHL compared with HCL subjects. Cholesteryl ester transfer protein (CETP) activity was postprandially enhanced only in MHL patients, and this elevation persisted in the late period (+19% at 12 hours, P<.05), sustaining the delayed enrichment of VLDL with cholesteryl ester (CE). The late postprandial period in MHL patients was also characterized by high levels of apolipoprotein B (apoB)-containing lipoproteins with apoCIII ([LpB:CIII] +36% at 12 hours, P<.01) and decreased levels of apoCIII contained in HDL ([LpCIII-HDL] -34% at 12 hours, P<.01), reflecting probably a defective return of apoCIII from TRL toward HDL. In MHL compared with HCL patients, decreased HDL2 levels were related to both HDL2b and HDL2a subpopulations (-57% and -49%, respectively, P<.01 for both) and decreased apoA-I levels (-53%, P<.01) were equally linked to decreased HDL2 with apoA-I only (LpA-I) and HDL2 with both apoA-I and apoA-II ([LpA-I:A-II] -55% and -52%, respectively, P<.01 for both). The significant inverse correlations between the postprandial magnitude of LpB:CIII and HDL2-LpA-I and HDL2b levels in MHL patients underline the close TRL-HDL interrelationships. Our findings indicate that TRL and HDL abnormalities evidenced at fasting were postprandially amplified, tightly interrelated, and persistent during the late fed period in mixed hyperlipidemia. Thus, these fasting abnormalities are likely postprandially originated and may constitute proatherogenic lipoprotein disorders additional to the HCL in MHL patients.

Macular xanthophylls, lipoprotein-related genes, and age-related macular degeneration1234

Science.gov (United States)

Koo, Euna; Neuringer, Martha; SanGiovanni, John Paul

2014-01-01

Plant-based macular xanthophylls (MXs; lutein and zeaxanthin) and the lutein metabolite meso-zeaxanthin are the major constituents of macular pigment, a compound concentrated in retinal areas that are responsible for fine-feature visual sensation. There is an unmet need to examine the genetics of factors influencing regulatory mechanisms and metabolic fates of these 3 MXs because they are linked to processes implicated in the pathogenesis of age-related macular degeneration (AMD). In this work we provide an overview of evidence supporting a molecular basis for AMD-MX associations as they may relate to DNA sequence variation in AMD- and lipoprotein-related genes. We recognize a number of emerging research opportunities, barriers, knowledge gaps, and tools offering promise for meaningful investigation and inference in the field. Overviews on AMD- and high-density lipoprotein (HDL)–related genes encoding receptors, transporters, and enzymes affecting or affected by MXs are followed with information on localization of products from these genes to retinal cell types manifesting AMD-related pathophysiology. Evidence on the relation of each gene or gene product with retinal MX response to nutrient intake is discussed. This information is followed by a review of results from mechanistic studies testing gene-disease relations. We then present findings on relations of AMD with DNA sequence variants in MX-associated genes. Our conclusion is that AMD-associated DNA variants that influence the actions and metabolic fates of HDL system constituents should be examined further for concomitant influence on MX absorption, retinal tissue responses to MX intake, and the capacity to modify MX-associated factors and processes implicated in AMD pathogenesis. PMID:24829491

Regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase expression by Zingiber officinale in the liver of high-fat diet-fed rats.

Science.gov (United States)

Nammi, Srinivas; Kim, Moon S; Gavande, Navnath S; Li, George Q; Roufogalis, Basil D

2010-05-01

Zingiber officinale has been used to control lipid disorders and reported to possess remarkable cholesterol-lowering activity in experimental hyperlipidaemia. In the present study, the effect of a characterized and standardized extract of Zingiber officinale on the hepatic lipid levels as well as on the hepatic mRNA and protein expression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was investigated in a high-fat diet-fed rat model. Rats were treated with an ethanol extract of Zingiber officinale (400 mg/kg) extract along with a high-fat diet for 6 weeks. The extract of Zingiber officinale significantly decreased hepatic triglyceride and tended to decrease hepatic cholesterol levels when administered over 6 weeks to the rats fed a high-fat diet. We found that in parallel, the extract up-regulated both LDL receptor mRNA and protein level and down-regulated HMG-CoA reductase protein expression in the liver of these rats. The metabolic control of body lipid homeostasis is in part due to enhanced cholesterol biosynthesis and reduced expression of LDL receptor sites following long-term consumption of high-fat diets. The present results show restoration of transcriptional and post-transcriptional changes in low-density lipoprotein and HMG CoA reductase by Zingiber officinale administration with a high-fat diet and provide a rational explanation for the effect of ginger in the treatment of hyperlipidaemia.

High-Density Lipoproteins and the Immune System

Directory of Open Access Journals (Sweden)

Hidesuke Kaji

2013-01-01

Full Text Available High-density lipoprotein (HDL plays a major role in vasodilation and in the reduction of low-density lipoprotein (LDL oxidation, inflammation, apoptosis, thrombosis, and infection; however, HDL is now less functional in these roles under certain conditions. This paper focuses on HDL, its anti-inflammation behavior, and the mechanisms by which HDL interacts with components of the innate and adaptive immune systems. Genome-wide association studies (GWAS and proteomic studies have elucidated important molecules involved in the interaction between HDL and the immune system. An understanding of these mechanisms is expected to be useful for the prevention and treatment of chronic inflammation due to metabolic syndrome, atherosclerosis, or various autoimmune diseases.

Low density lipoprotein receptor gene Ava II polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

Directory of Open Access Journals (Sweden)

Wu Dong-Feng

2011-02-01

Full Text Available Abstract Background Several common genetic polymorphisms in the low density lipoprotein receptor (LDL-R gene have associated with modifications of serum total cholesterol (TC and low density lipoprotein cholesterol (LDL-C levels, but the results are not consistent in different populations. Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was undertaken to detect the association of LDL-R gene Ava Ⅱ polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 1024 subjects of Bai Ku Yao and 792 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the LDL-R gene Ava Ⅱ polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum TC, high density lipoprotein cholesterol (HDL-C, LDL-C, apolipoprotein (Apo A1 and the ratio of ApoA1 to ApoB were lower in Bai Ku Yao than in Han (P - and A+ alleles was 65.5% and 34.5% in Bai Ku Yao, and 80.7% and 19.3% in Han (P -A-, A-A+ and A+A+ genotypes was 42.6%, 45.9% and 11.5% in Bai Ku Yao, and 64.9%, 31.6% and 3.5% in Han (P P 3.20 mmol/L subgroups in Bai Ku Yao (P P P P +A+ genotype had higher serum LDL-C, TC, HDL-C or ApoA1 levels than the subjects with A-A+ and A-A- genotypes. Spearman rank correlation analysis revealed that the levels of LDL-C in Bai Ku Yao and HDL-C in Han were correlated with genotypes (P P Conclusions The association of LDL-R gene Ava Ⅱ polymorphism and serum lipid levels is different between the Bai Ku Yao and Han populations. The discrepancy might partly result from different LDL-R gene Ava Ⅱ polymorphism or LDL-R gene-enviromental interactions.

Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hypercholesterolemia

NARCIS (Netherlands)

Sjouke, B.; Yahya, R.; Tanck, M.W.T.; Defesche, J.C.; Graaf, J. de; Wiegman, A.; Kastelein, J.J.; Mulder, M.T.; Hovingh, G.K.; Roeters van Lennep, J.E.

2017-01-01

BACKGROUND: Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and

Pharmacologic management of isolated low high-density lipoprotein syndrome.

Science.gov (United States)

Bermúdez, Valmore; Cano, Raquel; Cano, Clímaco; Bermúdez, Fernando; Arraiz, Nailet; Acosta, Luis; Finol, Freddy; Pabón, María Rebeca; Amell, Anilsa; Reyna, Nadia; Hidalgo, Joaquin; Kendall, Paúl; Manuel, Velasco; Hernández, Rafael

2008-01-01

High-density lipoprotein (HDL) cholesterol is a heterogeneous group of lipoproteins exhibiting a variety of properties like prostacyclin production stimulation, decrease in platelet aggregation, endothelial cell apoptosis inhibition, and low-density lipoprotein oxidation blockade. Epidemiologic studies have shown an inverse relation between HDL cholesterol levels and cardiovascular risk. Low HDL cholesterol is associated with increased risk for myocardial infarction, stroke, sudden death, peripheral artery disease, and postangioplasty restenosis. In contrast, high HDL levels are associated with longevity and protection against atherosclerotic disease development. Given the evolving epidemic of obesity, diabetes mellitus, and metabolic syndrome, the prevalence of low HDL will continue to rise. In the United States, low HDL is present in 35% of men, 15% of women, and approximately 63% of patients with coronary artery disease. Data extracted from the Framingham study highlight that 1-mg increase in HDL levels decreases by 2% to 3% the risk of cardiovascular disease. There is no doubt regarding clinical importance about isolated low HDL, but relatively few clinicians consider a direct therapeutic intervention of this dyslipidemia. In this sense, lifestyle measures should be the first-line strategy to manage low HDL levels. On the other hand, pharmacologic options include niacin, fibrates, and statins. Fibrates appear to reduce risk preferentially in patients with low HDL with metabolic syndrome, whereas statins reduce risk across all levels of HDL. Torcetrapib, a cholesteryl esters transfer protein inhibitor, represented a hope to raise this lipoprotein; however, all clinical trials on this drug had ceased after ILLUMINATE, RADIANCE and ERASE trials had recorded an increase in mortality, rates of myocardial infarction, angina, and heart failure. In the near future, drugs as beta-glucans, Apo-A1 mimetic peptides, and ACAT inhibitors, are the new promises to treat this

Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hypercholesterolemia

NARCIS (Netherlands)

Sjouke, Barbara; Yahya, Reyhana; Tanck, Michael W. T.; Defesche, Joep C.; de Graaf, Jacqueline; Wiegman, Albert; Kastelein, John J. P.; Mulder, Monique T.; Hovingh, G. Kees; Roeters van Lennep, Jeanine E.

2017-01-01

Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and in some

Inhibitory Effects of North American Wild Rice on Monocyte Adhesion and Inflammatory Modulators in Low-Density Lipoprotein Receptor-Knockout Mice.

Science.gov (United States)

Moghadasian, Mohammed H; Zhao, Ruozhi; Ghazawwi, Nora; Le, Khuong; Apea-Bah, Franklin B; Beta, Trust; Shen, Garry X

2017-10-18

The present study examined the effects of wild rice on monocyte adhesion, inflammatory and fibrinolytic mediators in low-density lipoprotein receptor-knockout (LDLr-KO) mice. Male LDLr-KO mice received a cholesterol (0.06%, w/w)-supplemented diet with or without white or wild rice (60%, w/w) for 20 weeks. White rice significantly increased monocyte adhesion and abundances of monocyte chemoattractant protein-1, tissue necrosis factor-α, intracellular cell adhesion molecule-1, plasminogen activator inhibitor-1, urokinase plasminogen activator (uPA), and uPA receptor in aortae and hearts of LDLr-KO mice compared to the control diet. Wild rice inhibited monocyte adhesion to the aorta, atherosclerosis, and abundances of the inflammatory and fibrinolytic regulators in the cardiovascular tissue of LDLr-KO mice compared to white rice. White or wild rice did not significantly alter the levels of cholesterol, triglycerides, or antioxidant enzymes in plasma. The anti-atherosclerotic effect of wild rice may result from its inhibition on monocyte adhesion and inflammatory modulators in LDLr-KO mice.

L-Cysteine-induced up-regulation of the low-density lipoprotein receptor is mediated via a transforming growth factor-alpha signalling pathway.

Science.gov (United States)

Tanaka, Yuma; Shimada, Masaya; Nagaoka, Satoshi

2014-02-14

Sulphur-containing amino acids regulate plasma cholesterol levels in animals and humans. However, their mechanism of action remains unclear. Low-density lipoprotein receptor (LDLR) plays an important role in cholesterol metabolism. We therefore investigated the effects of sulphur-containing amino acids on the expression of LDLR in hepatocytes. HepG2 cells were cultured in Dulbecco's Modified Eagle's Medium with or without sulphur-containing amino acids and cysteine-containing compounds. We found that L-cysteine increased LDLR mRNA and enhanced LDLR gene promoter activity through the extracellular-signal-related kinase and p38 mitogen-activated protein kinase signalling pathways in HepG2 cells. Moreover, we observed that L-cysteine stimulated the release of transforming growth factor-alpha (TGF-α) and that TGF-α increased the LDLR mRNA levels. This study provides a report of the L-cysteine mediated up-regulation of the LDLR expression via TGF-α signalling pathway. Our findings provide insights into cholesterol homeostasis and amino acid signalling. Copyright © 2014 Elsevier Inc. All rights reserved.

A receptor-based biosensor for lipoprotein docking at the endothelial surface and vascular matrix.

Science.gov (United States)

Siegel, G; Malmsten, M; Klüssendorf, D; Michel, F

2001-12-01

Proteoheparan sulfate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, representing a receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques showing that HDL has a high binding affinity to the receptor and a protective effect on interfacial heparan sulfate proteoglycan layers, with respect to LDL and Ca(2+) complexation. LDL was found to deposit strongly at the proteoheparan sulfate, particularly in the presence of Ca(2+), thus creating the complex formation "proteoglycan-low density lipoprotein-calcium". This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. On the other hand, HDL bound to heparan sulfate proteoglycan protected against LDL docking and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL and aqueous garlic extract were able to reduce the ternary complex deposition and to disintegrate HS-PG/LDL/Ca(2+) aggregates. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a "nanoscopic" level under close to physiological conditions. In particular, Ca(2+)-promoted LDL deposition and the protective effect of HDL, even at high Ca(2+) and LDL concentrations, agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis. Therefore, we believe that the system can be of some use in investigations, e.g. of the interplay between different lipoproteins in arteriosclerotic

The Influence of Decreased Levels of High Density Lipoprotein ...

African Journals Online (AJOL)

Background: Changes in lipoproteins levels in sickle cell disease (SCD) patients are well.known, but the physiological ramifications of the low levels observed have not been entirely resolved. Aim: The aim of this study is to evaluate the impact of decreased levels of high density lipoprotein cholesterol (HDL.c) on ...

High Density Lipoprotein and it's Dysfunction.

Science.gov (United States)

Eren, Esin; Yilmaz, Necat; Aydin, Ozgur

2012-01-01

Plasma high-density lipoprotein cholesterol(HDL-C) levels do not predict functionality and composition of high-density lipoprotein(HDL). Traditionally, keeping levels of low-density lipoprotein cholesterol(LDL-C) down and HDL-C up have been the goal of patients to prevent atherosclerosis that can lead to coronary vascular disease(CVD). People think about the HDL present in their cholesterol test, but not about its functional capability. Up to 65% of cardiovascular death cannot be prevented by putative LDL-C lowering agents. It well explains the strong interest in HDL increasing strategies. However, recent studies have questioned the good in using drugs to increase level of HDL. While raising HDL is a theoretically attractive target, the optimal approach remains uncertain. The attention has turned to the quality, rather than the quantity, of HDL-C. An alternative to elevations in HDL involves strategies to enhance HDL functionality. The situation poses an opportunity for clinical chemists to take the lead in the development and validation of such biomarkers. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport (RCT). The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High antioxidant and anti-inflammatory activities of HDL are associated with protection from CVD.This review addresses the current state of knowledge regarding assays of HDL functions and their relationship to CVD. HDL as a therapeutic target is the new frontier with huge potential for positive public health implications.

High-density lipoproteins and adrenal steroidogenesis : A population-based study

NARCIS (Netherlands)

Buitenwerf, Edward; Kerstens, Michiel N.; Links, Thera P.; Kema, Ido P.; Dullaart, Robin P. F.

BACKGROUND: Cholesterol trafficked within plasma lipoproteins, in particular high-density lipoproteins (HDL), may represent an important source of cholesterol that is required for adrenal steroidogenesis. Based on a urinary gas chromatography method, compromised adrenal function has been suggested

Characterization of a family of gamma-ray-induced CHO mutants demonstrates that the ldlA locus is diploid and encodes the low-density lipoprotein receptor

International Nuclear Information System (INIS)

Sege, R.D.; Kozarsky, K.F.; Krieger, M.

1986-01-01

The ldlA locus is one of four Chinese hamster ovary (CHO) cell loci which are known to be required for the synthesis of functional low-density lipoprotein (LDL) receptors. Previous studies have suggested that the ldlA locus is diploid and encodes the LDL receptor. To confirm this assignment, we have isolated a partial genomic clone of the Chinese hamster LDL receptor gene and used this and other nucleic acid and antibody probes to study a family of ldlA mutants isolated after gamma-irradiation. Our analysis suggests that there are two LDL receptor alleles in wild-type CHO cells. Each of the three mutants isolated after gamma-irradiation had detectable deletions affecting one of the two LDL receptor alleles. One of the mutants also had a disruption of the remaining allele, resulting in the synthesis of an abnormal receptor precursor which was not subject to Golgi-associated posttranslational glycoprotein processing. The correlation of changes in the expression, structure, and function of LDL receptors with deletions in the LDL receptor genes in these mutants directly demonstrated that the ldlA locus in CHO cells is diploid and encodes the LDL receptor. In addition, our analysis suggests that CHO cells in culture may contain a partial LDL receptor pseudogene

Association of triglyceride-rich lipoproteins-related markers and low-density lipoprotein heterogeneity with cardiovascular risk: effectiveness of polyacrylamide-gel electrophoresis as a method of determining low-density lipoprotein particle size.

Science.gov (United States)

Tani, Shigemasa; Matsumoto, Michiaki; Nagao, Ken; Hirayama, Atsushi

2014-01-01

Despite well-controlled low-density lipoprotein cholesterol (LDL-C), hypertriglyceridemia is an independent predictor of coronary events. We investigated the risk of atherosclerotic cardiovascular disease through examining the relation between triglyceride (TG) metabolism and LDL-heterogeneity as assessed by polyacrylamide-gel electrophoresis (PAGE). Estimated LDL-particle size [relative LDL migration (LDL-Rm value)] measured by PAGE with the LipoPhor system (Joko, Tokyo, Japan) was evaluated in 645 consecutive patients with one additional risk factor for atherosclerotic cardiovascular disease.Multivariate regression analysis after adjustments for traditional risk factors revealed an elevated triglyceride-rich lipoproteins (TRLs)-related markers [TG, remnant-like particle cholesterol (RLP-C), very LDL (VLDL) fraction, apolipoprotein (apo) C-II, and apo C-III] level to be an independent predictor of smaller-size LDL-particle size, both in the overall population, and in a subset of patients with serum LDL-C <100 mg/dL. Even among the patients with LDL-C levels <100 mg/dL, the serum levels of atherogenic lipid markers in those with a LDL-Rm value ≥0.40, suggesting the presence of large amounts of small-dense LDL and upper limit (mean+2 standard deviation) in this population, were significantly higher than in those with a LDL-Rm value <0.40. Moreover, the serum levels of TRLs-related markers showed high accurate area under the receiver-operating characteristic curve (TG, 0.896; RLP-C, 0.875; VLDL fraction, 0.803; apo C-II, 0.778; and apo C-III, 0.804, respectively) in terms of evaluation of the indicators of LDL-Rm value ≥0.40. To further reduce the risk of atherosclerotic cardiovascular disease, it may be of particular importance to pay attention not only to the quantitative change in the serum LDL-C, but also TG-metabolism associated with LDL-heterogeneity. Combined evaluation of TRLs-related markers and LDL-Rm value may be useful for assessing the risk of

Geometrical separation method for lipoproteins using bioformulated-fiber matrix electrophoresis: size of high-density lipoprotein does not reflect its density.

Science.gov (United States)

Tabuchi, Mari; Seo, Makoto; Inoue, Takayuki; Ikeda, Takeshi; Kogure, Akinori; Inoue, Ikuo; Katayama, Shigehiro; Matsunaga, Toshiyuki; Hara, Akira; Komoda, Tsugikazu

2011-02-01

The increasing number of patients with metabolic syndrome is a critical global problem. In this study, we describe a novel geometrical electrophoretic separation method using a bioformulated-fiber matrix to analyze high-density lipoprotein (HDL) particles. HDL particles are generally considered to be a beneficial component of the cholesterol fraction. Conventional electrophoresis is widely used but is not necessarily suitable for analyzing HDL particles. Furthermore, a higher HDL density is generally believed to correlate with a smaller particle size. Here, we use a novel geometrical separation technique incorporating recently developed nanotechnology (Nata de Coco) to contradict this belief. A dyslipidemia patient given a 1-month treatment of fenofibrate showed an inverse relationship between HDL density and size. Direct microscopic observation and morphological observation of fractionated HDL particles confirmed a lack of relationship between particle density and size. This new technique may improve diagnostic accuracy and medical treatment for lipid related diseases.

Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake.

Science.gov (United States)

Friday, K E; Drinkwater, B L; Bruemmer, B; Chesnut, C; Chait, A

1993-12-01

To determine the interactive effects of hormones, exercise, and diet on plasma lipids and lipoproteins, serum estrogen and progesterone levels, nutrient intake, and plasma lipid, lipoprotein, and apolipoprotein concentrations were measured in 24 hypoestrogenic amenorrheic and 44 eumenorrheic female athletes. When compared to eumenorrheic athletes, amenorrheic athletes had higher levels of plasma cholesterol (5.47 +/- 0.17 vs. 4.84 +/- 0.12 mmol/L, P = 0.003), triglyceride (0.75 +/- 0.06 vs. 0.61 +/- 0.03 mmol/L, P = 0.046), low-density lipoprotein (LDL; 3.16 +/- 0.15 vs. 2.81 +/- 0.09 mmol/L, P = 0.037), high-density lipoprotein (HDL; 1.95 +/- 0.07 vs. 1.73 +/- 0.05 mmol/L, P = 0.007), and HDL2 (0.84 +/- 0.06 vs. 0.68 +/- 0.04 mmol/L, P = 0.02) cholesterol. Plasma LDL/HDL cholesterol ratios, very low-density lipoprotein and HDL3 cholesterol, and apolipoprotein A-I and A-II levels were similar in the two groups. Amenorrheic athletes consumed less fat than eumenorrheic subjects (52 +/- 5 vs. 75 +/- 3 g/day, P = 0.02), but similar amounts of calories, cholesterol, protein, carbohydrate, and ethanol. HDL cholesterol levels in amenorrheic subjects correlated positively with the percent of dietary calories from fat (r = 0.42, n = 23, P = 0.045) but negatively with the percent from protein (r = -0.49, n = 23, P = 0.017). Thus, exercise-induced amenorrhea may adversely affect cardiovascular risk by increasing plasma LDL and total cholesterol. However, cardioprotective elevations in plasma HDL and HDL2 cholesterol may neutralize the risk of cardiovascular disease in amenorrheic athletes.

Obtention of scintillography images by low density lipoproteins labelled with technetium 99

International Nuclear Information System (INIS)

Silva, S.; Coelho, I.; Zanardo, E.; Pileggi, F.; Meneguethi, C.; Maranhao, R.C.

1992-01-01

The low density lipoproteins carry the most part of the cholesterol in the blood plasma. These lipoproteins are labelled with technetium-99-m and have been used for obtaining images in nuclear medicine. The introduction of this technique is presented, aiming futures clinical uses. Scintillographic images are obtained 25 minutes and 24 hours after the injection of 3 m Ci of low density lipoproteins - technetium-99 m in rabbits. (C.G.C.)

Two novel mutations in exon 3 and 4 of low density lipoprotein (LDL) receptor gene in patients with heterozygous familial hypercholesterolemia

International Nuclear Information System (INIS)

Khan, S.P.

2011-01-01

Objective: To determine the common mutation of low density lipoprotein receptor in hypercholesterolemia patients requiring screening for heterozygous familial hypercholesterolemia (HeFH) in Karachi. Study Design: Case-series. Place and Duration of Study: Dr. Ziauddin Hospital Laboratory and Dr. Rubina Ghani's Pathological and Molecular Laboratories, Karachi, for the PCR bench work from June 2008 to October 2009. Methodology: All the patients selected for this study were from Dr. Ziauddin Hospital and National Institute of Cardiovascular Diseases. All the patients having high total cholesterol and LDL-cholesterol were included in this study with premature coronary artery diseases or a family history of hypercholesterolemia. Exclusion criteria included Diabetes mellitus, hypertension, renal disease, hypothyroidism and steroid therapy. After lipid profile with overnight fasting, DNA was extracted from whole blood collected in EDTA (ethylenediamine tetra acetic acid) tube and multiplex PCR (polymerase chain reaction) using forward and reverse primers of exons 3, 4, 9 and 14 of base pairs 162, 431, 550 and 496 respectively. Results: Out of total of 120 hypercholesterolemia cases, 42 patients were classical cases of HeFH (heterozygous familial hypercholesterolemia) with xanthomas, xanthelasmas and LDL-C > 160 mg/dl. The total cholesterol (260 +- 57 mg/dL) and LDL-C (192 +- 39 mg/dL ) of cases was significantly high as compared to, controls having total cholesterol (184 9 +- 27 mg/dL) and LDL-C (105 +- 22 mg/dL), p > 0.001. Two novel point mutations were noted in exon 3 and exon 4. The other 78 cases were probable with raised LDL-C (low density lipoprotein cholesterol) and family history of premature coronary heart diseases. Conclusion: The frequency of HeFH was 35% classical and 65% probable cases out of total 120 hypercholesterolemia patients from two tertiary care hospitals in Karachi. The point mutation on exon 3 and exon 4 of LDLR gene was the most common. PCR is

Activation of lipoprotein lipase by lipoprotein fractions of human serum.

Science.gov (United States)

Bier, D M; Havel, R J

1970-11-01

Triglycerides in fat emulsions are hydrolyzed by lipoprotein lipase only when they are "activated" by serum lipoproteins. The contribution of different lipoprotein fractions to hydrolysis of triglycerides in soybean oil emulsion was assessed by determining the quantity of lipoprotein fraction required to give half-maximal hydrolysis. Most of the activator property of whole serum from normolipidemic, postabsorptive subjects was in high density lipoproteins. Low density lipoproteins and serum from which all lipoprotein classes were removed had little or no activity. Also, little activator was present in guinea pig serum or in very low density poor serum from an individual with lecithin:cholesterol acyltransferase deficiency, both of which are deficient in high density lipoproteins. Human very low density lipoproteins are potent activators and are much more active than predicted from their content of high density lipoprotein-protein. Per unit weight of protein, very low density lipoproteins had 13 times the activity of high density lipoproteins. These observations suggest that one or more of the major apoproteins of very low density lipoproteins, present as a minor constituent of high density lipoproteins, may be required for the activation process.

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

NARCIS (Netherlands)

Chapman, M. John; Ginsberg, Henry N.; Amarenco, Pierre; Andreotti, Felicita; Borén, Jan; Catapano, Alberico L.; Descamps, Olivier S.; Fisher, Edward; Kovanen, Petri T.; Kuivenhoven, Jan Albert; Lesnik, Philippe; Masana, Luis; Nordestgaard, Børge G.; Ray, Kausik K.; Reiner, Zeljko; Taskinen, Marja-Riitta; Tokgözoglu, Lale; Tybjærg-Hansen, Anne; Watts, Gerald F.

2011-01-01

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

DEFF Research Database (Denmark)

Chapman, M John; Ginsberg, Henry N; Amarenco, Pierre

2011-01-01

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipop...

High-Density Lipoprotein Function in Exudative Age-Related Macular Degeneration.

Directory of Open Access Journals (Sweden)

Laura Pertl

Full Text Available High-density lipoproteins (HDL have long been implicated in the pathogenesis of age-related macular degeneration (AMD. However, conflicting results have been reported with regard to the associations of AMD with HDL-cholesterol levels. The present study is the first to assess HDL composition and metrics of HDL function in patients with exudative AMD and control patients.Blood samples were collected from 29 patients with exudative AMD and 26 age-matched control patients. Major HDL associated apolipoproteins were determined in apoB-depleted serum by immunoturbidimetry or ELISA, HDL-associated lipids were quantified enzymatically. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function, including cholesterol efflux capacity, anti-oxidative and anti-inflammatory activities using apoB-depleted serum from study participants.In our study, we observed that the HDL associated acute phase protein serum amyloid A (SAA was significantly increased in AMD patients (p<0.01, whereas all other assessed apolipoproteins including ApoA-I, apoA-II, apoC-II, apoC-III and apoE as well as major HDL associated lipids were not altered. HDL efflux capacity, anti-oxidative capacity and arylesterase activity were not different in AMD patients when compared with the control group. The ability of apoB-depleted serum to inhibit monocyte NF-κB expression was significantly improved in AMD patients (mean difference (MD -5.6, p<0.01. Moreover, lipoprotein-associated phospholipase A2 activity, a marker of vascular inflammation, was decreased in AMD subjects (MD -24.1, p<0.01.The investigated metrics of HDL composition and HDL function were not associated with exudative AMD in this study, despite an increased content of HDL associated SAA in AMD patients. Unexpectedly, anti-inflammatory activity of apoB-depleted serum was even increased in our study. Our data suggest that the investigated parameters of serum HDL function showed no

Low-Density Lipoprotein Modified by Myeloperoxidase in Inflammatory Pathways and Clinical Studies

Directory of Open Access Journals (Sweden)

Cédric Delporte

2013-01-01

Full Text Available Oxidation of low-density lipoprotein (LDL has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNFα and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

Utility of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) in the postmortem diagnosis of ischemic heart disease.

Science.gov (United States)

Takasu, Shojiro; Matsumoto, Sari; Kanto, Yuko; Iwadate, Kimiharu

2018-04-01

Ischemic heart disease (IHD) is a major cause of death in developed countries. Postmortem IHD diagnosis using biochemical markers is difficult because of the postmortem changes. In the present study, we investigated the utility of soluble lectin-like low-density lipoprotein receptor-1 (sLOX-1) in body fluids obtained from forensic autopsy cases. We measured pericardial fluid, urine, and serum sLOX-1 levels; these samples were obtained from medicolegal autopsy cases (n = 149, postmortem interval fluid and urine of patients with acute IHD had higher sLOX-1 levels (p fluid and urine samples obtained postmortem are useful markers of acute IHD. Copyright © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Epidemiological reference ranges for low-density lipoprotein ...

African Journals Online (AJOL)

Although there is widespread acceptance that total cholesterol (TC) value reference ranges should be based on epidemiological rather than statistical considerations, the epidemiological action limits for Iow-density lipoprotein cholesterol (LDL-C) are still incomplete and only statistical reference ranges for apolipoprotein B ...

High-density lipoprotein-like particle formation of Synuclein variants.

Science.gov (United States)

Eichmann, Cédric; Kumari, Pratibha; Riek, Roland

2017-01-01

α-Synuclein (α-Syn) is an intrinsically disordered protein in solution whose fibrillar aggregates are the hallmark of Parkinson's disease (PD). Although the specific function of α-Syn is still unclear, its high structural plasticity is key for the interactions of α-Syn with biological membranes. Recently, it has been observed that α-Syn is able to form high-density lipoprotein-like (HDL-like) particles that are reminiscent of self-assembling phospholipid bilayer nanodiscs. Here, we extended our preparation method for the production of α-Syn lipoprotein particles to the β- and γ-Syn variants, and the PD-related familial α-Syn mutants. We show that all human Syns can form stable and homogeneous populations of HDL-like particles with distinct morphologies. Our results characterize the impact of the individual Syns on the formation capacity of these particles and indicate that Syn HDL-like particles are neither causing toxicity nor a toxicity-related loss of α-Syn in PD. © 2016 Federation of European Biochemical Societies.

Comparison of soymilk and probiotic soymilk effects on serum high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in diabetic Wistar rats

Directory of Open Access Journals (Sweden)

Mina Babashahi

2015-04-01

Full Text Available BACKGROUND: Soy milk (SM and its fermented products are identified as rich sources of bioactive compounds helping to manage and to reduce the risk of chronic disease. This study aimed to compare the effects of SM and probiotic SM (PSM consumption on serum low-density lipoprotein cholesterol (LDL-C and high-density lipoprotein cholesterol (HDL-C in diabetic Wistar rats. METHODS: Probiotic SM was prepared by fermentation of the plain SM with a native strain of Lactobacillus plantarum. 20 streptozotocin-nicotinamide-induced diabetic Wistar rats were divided into two groups based on the type of administered SM (SM group and PSM group. The animals were fed with 1 ml/day of either soy or PSM for 21 days. The serum lipoprotein levels were analyzed at baseline and the end of the intervention period. RESULTS: HDL-C increased significantly in PSM group. Furthermore, this group showed more percent of change in increased HDL-C in compression with SM group (P < 0.050. Regarding LDL-C level, rats fed with SM was not significantly different from the PSM group (P < 0.050; though, this biomarker was reduced in both group. CONCLUSION: Probiotic SM could modulate blood lipoprotein levels. Thus, it may be considered in managing diabetes complications and atherosclerotic risks. 

In vitro biological efficacy of boronated low density lipoproteins for NCT

International Nuclear Information System (INIS)

Kahl, S.B.; Pate, D.; Laster, B.H.; Popenoe, E.A.; Fairchild, R.G.

1992-01-01

Low Density Lipoproteins (LDLs) are known to be internalized within the cell by receptor-mediated mechanisms. There is evidence that LDLs may be taken up avidly by tumor cells to provide cholesterol for the synthesis of cell membrane. Thus, the possibility exists that LDLs may provide an ideal vehicle for the transport of boron to tumor cells for Neutron Capture Therapy (NCT). A boronated analog of LDL has recently been synthesized for possible application in NCT. The analog was tested in cell culture for uptake and biological efficacy in the thermal neutron beam at the Brookhaven Medical Research Reactor (BMRR). It was found that boron concentrations ten times higher than that required for NCT were easily obtained, and that uptake data were constant with a receptor mediated binding mechanism. The measured intracellular concentration of ∼240 μg 10 B/g cells is significantly higher than that obtained with any other boron compound previously evaluated for possible clinical application

Loci of catabolism of beta-very low density lipoprotein in vivo delineated with a residualizing label, 125I-dilactitol tyramine

International Nuclear Information System (INIS)

Daugherty, A.; Thorpe, S.R.; Lange, L.G.; Sobel, B.E.; Schonfeld, G.

1985-01-01

beta-Very low density lipoprotein (beta-VLDL) may be a major atherogenic lipoprotein, and knowledge of the sites of its catabolism should facilitate elucidation of mechanisms important in the regulation of its plasma concentrations. In this study, catabolic sites of beta-VLDL have been delineated in normolipidemic rabbits with a novel, radioiodinated, residualizing label, 125 I-dilactitol tyramine ( 125 I-DLT). Comparative studies of beta-VLDL and low density lipoprotein catabolism were performed with 125 I-DLT conjugated to each lipoprotein and with lipoproteins iodine-labeled conventionally. Conjugation did not alter size distributions or charge characteristics of lipoprotein particles. The overall processing (binding and degradation) of lipoproteins by cultured rabbit skin fibroblasts was not influenced by 125 I-DLT derivatization, suggesting that attachment of the label did not influence cell receptor-lipoprotein interactions. Furthermore, although degradation products of 125 I-lipoproteins leaked out of the cells and into the medium, the degradation products of 125 I-DLT lipoproteins were retained by the cells. The principal catabolic site of beta-VLDL in normolipidemic rabbits was found to be the liver with 54 +/- 4% of injected 125 I retained in this organ 24 h after injection of 125 I-DLT-beta-VLDL. When catabolism was normalized to tissue weight, the liver and adrenals were found to be approximately equally active in the metabolism of beta-VLDL. In agreement with results of other studies with residualizing labels, the principal organ of catabolism of 125 I-DLT-LDL in vivo was the liver. The adrenals were the most highly catabolizing organ when results were normalized for tissue weight

Dietary fish oil stimulates hepatic low density lipoprotein transport in the rat.

Science.gov (United States)

Ventura, M A; Woollett, L A; Spady, D K

1989-01-01

These studies were undertaken to examine the effect of fish oil, safflower oil, and hydrogenated coconut oil on the major processes that determine the concentration of low density lipoprotein (LDL) in plasma, i.e., the rate of LDL production and the rates of receptor-dependent and receptor-independent LDL uptake in the various organs of the body. When fed at the 20% level, fish oil reduced plasma LDL-cholesterol levels by 38% primarily by increasing LDL receptor activity in the liver. Dietary safflower oil also increased hepatic LDL receptor activity; however, since the rate of LDL production also increased, plasma LDL-cholesterol levels remained essentially unchanged. Hydrogenated coconut oil had no effect on LDL receptor activity but increased the rate of LDL-cholesterol production causing plasma LDL-cholesterol levels to increase 46%. Dietary fish oil had no effect on the receptor-dependent transport of asialofetuin by the liver, suggesting that the effect of fish oil on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physical properties of hepatic membranes. Finally, dietary fish oil increased hepatic cholesteryl ester levels and suppressed hepatic cholesterol synthesis rates, suggesting that the up-regulation of hepatic LDL receptor activity in these animals was not simply a response to diminished cholesterol availability in the liver. PMID:2760200

Ultrasound-targeted microbubble destruction improves the low density lipoprotein receptor gene expression in HepG2 cells

International Nuclear Information System (INIS)

Guo Dongping; Li Xiaoyu; Sun, Ping; Tang Yibo; Chen Xiuying; Chen Qi; Fan Leming; Zang Bin; Shao Lizheng; Li Xiaorong

2006-01-01

Ultrasound-targeted microbubble destruction had been employed in gene delivery and promised great potential. Liver has unique features that make it attractive for gene therapy. However, it poses formidable obstacles to hepatocyte-specific gene delivery. This study was designed to test the efficiency of therapeutic gene transfer and expression mediated by ultrasound/microbubble strategy in HepG 2 cell line. Air-filled albumin microbubbles were prepared and mixed with plasmid DNA encoding low density lipoprotein receptor (LDLR) and green fluorescent protein. The mixture of the DNA and microbubbles was administer to cultured HepG 2 cells under variable ultrasound conditions. Transfection rate of the transferred gene and cell viability were assessed by FACS analysis, confocal laser scanning microscopy, Western blot analysis and Trypan blue staining. The result demonstrated that microbubbles with ultrasound irradiation can significantly elevate exogenous LDLR gene expression and the expressed LDLRs were functional and active to uptake their ligands. We conclude that ultrasound-targeted microbubble destruction has the potential to promote safe and efficient LDLR gene transfer into hepatocytes. With further refinement, it may represent an effective nonviral avenue of gene therapy for liver-involved genetic diseases

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

DEFF Research Database (Denmark)

Chapman, M John; Ginsberg, Henry N; Amarenco, Pierre

2011-01-01

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high......-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic...

The Impact of Cardiorespiratory Fitness on Age-Related Lipids and Lipoproteins

Science.gov (United States)

Park, Yong-Moon Mark; Sui, Xuemei; Liu, Junxiu; Zhou, Haiming; Kokkinos, Peter F.; Lavie, Carl J.; Hardin, James W.; Blair, Steven N.

2015-01-01

Background Evidence on the effect of cardiorespiratory fitness (CRF) on age-related longitudinal changes of lipids and lipoproteins is scarce. Objectives This study sought to assess the longitudinal, aging trajectory of lipids and lipoproteins for the life course in adults, and to determine whether CRF modifies the age-associated trajectory of lipids and lipoproteins. Methods Data came from 11,418 men, 20 to 90 years of age, without known high cholesterol, high triglycerides, cardiovascular disease, and cancer at baseline and during follow-up from the Aerobics Center Longitudinal Study. There were 43,821 observations spanning 2 to 25 (mean 3.5) health examinations between 1970 and 2006. CRF was quantified by a maximal treadmill exercise test. Marginal models using generalized estimating equations were applied. Results Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C) presented similar inverted U-shaped quadratic trajectories with aging: gradual increases were noted until the mid-40s to early 50s, with subsequent declines (all p lipoproteins in young to middle-aged men than in older men. Conclusions Our investigation reveals a differential trajectory of lipids and lipoproteins with aging according to CRF in healthy men, and suggests that promoting increased CRF levels may help delay the development of dyslipidemia. PMID:25975472

The effect of cardiorespiratory fitness on age-related lipids and lipoproteins.

Science.gov (United States)

Park, Yong-Moon Mark; Sui, Xuemei; Liu, Junxiu; Zhou, Haiming; Kokkinos, Peter F; Lavie, Carl J; Hardin, James W; Blair, Steven N

2015-05-19

Evidence on the effect of cardiorespiratory fitness (CRF) on age-related longitudinal changes of lipids and lipoproteins is scarce. This study sought to assess the longitudinal aging trajectory of lipids and lipoproteins for the life course in adults and to determine whether CRF modifies the age-associated trajectory of lipids and lipoproteins. Data came from 11,418 men, 20 to 90 years of age, without known high cholesterol, high triglycerides, cardiovascular disease, and cancer at baseline and during follow-up from the Aerobics Center Longitudinal Study. There were 43,821 observations spanning 2 to 25 health examinations (mean 3.5 examinations) between 1970 and 2006. CRF was quantified by a maximal treadmill exercise test. Marginal models using generalized estimating equations were applied. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides, and non-high-density lipoprotein cholesterol (non-HDL-C) presented similar inverted U-shaped quadratic trajectories with aging: gradual increases were noted until age mid-40s to early 50s, with subsequent declines (all p lipoproteins in young to middle-age men than in older men. Our investigation reveals a differential trajectory of lipids and lipoproteins with aging according to CRF in healthy men and suggests that promoting increased CRF levels may help delay the development of dyslipidemia. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

High-density lipoproteins: a novel therapeutic target for cardiovascular disease

Directory of Open Access Journals (Sweden)

TS Mohamed Saleem

2011-01-01

Full Text Available TS Mohamed Saleem1, PV Sandhya Rani1, K Gauthaman21Department of Pharmacology, Annamacharya College of Pharmacy, New Boyanapalli, Andhrapradesh, India; 2Department of Drug Technology, Faculty of Medical Technology, Derna, LibyaAbstract: Cardiovascular disease has a high rate of mortality in both Western and developing countries. Atherosclerosis and generation of reactive oxygen species through oxidative stress is the major risk factor for cardiovascular disease. Atherothrombosis with low levels of high-density lipoprotein (HDL and high levels of low-density lipoprotein is a major risk factor for atherosclerosis-induced cardiovascular disease. Lipid-lowering drugs like statins, niacin, fibrates, and some newer agents, ie, the apolipoprotein A-I mimetics and the cholesteryl ester transfer protein inhibitors, not only increase HDL levels but are also effective in reducing key atherogenic lipid components, including triglyceride-rich lipoproteins. The aim of this review is to discuss the accumulating evidence suggesting that HDL possesses a diverse range of biological actions, and that increasing HDL levels by drug treatment may be beneficial in the prevention of cardiovascular disease.Keywords: cardiovascular disease, lipoproteins, statins, apolipoprotein, atherosclerosis

Learning from biology: synthetic lipoproteins for drug delivery.

Science.gov (United States)

Huang, Huang; Cruz, William; Chen, Juan; Zheng, Gang

2015-01-01

Synthetic lipoproteins represent a relevant tool for targeted delivery of biological/chemical agents (chemotherapeutics, siRNAs, photosensitizers, and imaging contrast agents) into various cell types. These nanoparticles offer a number of advantages for drugs delivery over their native counterparts while retaining their natural characteristics and biological functions. Their ultra-small size (lipoprotein receptors, i.e., low-density lipoprotein receptor (LDLR) and Scavenger receptor class B member 1 (SRB1) that are found in a number of pathological conditions (e.g., cancer, atherosclerosis), make them superior delivery strategies when compared with other nanoparticle systems. We review the various approaches that have been developed for the generation of synthetic lipoproteins and their respective applications in vitro and in vivo. More specifically, we summarize the approaches employed to address the limitation on use of reconstituted lipoproteins by means of natural or recombinant apolipoproteins, as well as apolipoprotein mimetic molecules. Finally, we provide an overview of the advantages and disadvantages of these approaches and discuss future perspectives for clinical translation of these nanoparticles. © 2014 Wiley Periodicals, Inc.

Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women

Science.gov (United States)

The effect of hormone therapy (HT) on the plasma concentration of remnant lipoprotein cholesterol (RLP-C) and high density lipoprotein (HDL) subpopulations and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease (CHD) were examined in 256 postmen...

The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol

Directory of Open Access Journals (Sweden)

Poirier S

2013-10-01

Full Text Available Steve Poirier,1,2 Gaétan Mayer1–31Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, QC, Canada; 2Départements de Pharmacologie, 3Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC, CanadaAbstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9 directly binds to the epidermal growth factor-like repeat A domain of low-density lipoprotein receptor and induces its degradation, thereby controlling circulating low-density lipoprotein cholesterol (LDL-C concentration. Heterozygous loss-of-function mutations in PCSK9 can decrease the incidence of coronary heart disease by up to 88%, owing to lifelong reduction of LDL-C. Moreover, two subjects with PCSK9 loss-of-function mutations on both alleles, resulting in a total absence of functional PCSK9, were found to have extremely low circulating LDL-C levels without other apparent abnormalities. Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease. Recent clinical trials using anti-PCSK9 monoclonal antibodies that block the PCSK9:low-density lipoprotein receptor interaction were shown to considerably reduce LDL-C levels by up to 65% when given alone and by up to 72% in patients already receiving statin therapy. In this review, we will discuss how major scientific breakthroughs in PCSK9 cell biology have led to the development of new and forthcoming LDL-C-lowering pharmacological agents.Keywords: PCSK9, LDLR, LDL-cholesterol, lipoproteins, coronary heart disease, inhibitors, monoclonal antibody therapy

Neutrophil–lymphocyte ratio is associated with low high-density lipoprotein cholesterol in healthy young men

Directory of Open Access Journals (Sweden)

Duran Tok

2014-04-01

Full Text Available Objective: It has been reported that the neutrophil–lymphocyte ratio is significantly elevated in patients with low high-density lipoprotein cholesterol (<35 mg/dL. But in this study, some patients had hypertension that may have affected the neutrophil–lymphocyte ratio. This study consisted of 1274 asymptomatic healthy young men. In contrast with the previous study, we investigated the neutrophil–lymphocyte ratio in healthy young men with low high-density lipoprotein cholesterol compared with controls. Methods: We studied 1274 asymptomatic young males (military personnel screening who underwent routine health check-up. Of them, 102 subjects had low high-density lipoprotein cholesterol. Results: The neutrophil–lymphocyte ratio was significantly higher among the men with low high-density lipoprotein cholesterol than that of the control group (P < 0.001. Conclusion: We conclude that the neutrophil–lymphocyte ratio is significantly elevated in asymptomatic healthy young men with low high-density lipoprotein cholesterol compared with control participants.

Transfer of plasma lipoprotein components and of plasma proteins into aortas of cholesterol-fed rabbits. Molecular size as a determinant of plasma lipoprotein influx

International Nuclear Information System (INIS)

Stender, S.; Zilversmit, D.B.

1981-01-01

The arterial influx of esterified and free cholesterol from low density lipoproteins and very low density lipoproteins in 20 hypercholesterolemic rabbits was measured simultaneously by the use of lipoproteins labeled in vivo with [ 3 H]- and [ 14 C]-cholesterol. The simultaneous arterial influx of either [ 3 H]-leucine-labeled very low density lipoproteins, low density lipoproteins, high density lipoproteins, or plasma proteins was also measured in each rabbit. The arterial influx was calculated as intimal clearance, i.e., the influx of a given fraction divided by its plasma concentration. The intimal clearance of low density lipoprotein esterified cholesterol was equal to that for the apolipoproteins of that fraction, which is compatible with an arterial influx of intact low density lipoprotein molecules. The intimal clearance of very low density apolipoprotein or cholesteryl ester was less than that for low density lipoprotein, whereas high density lipoprotein and albumin clearances exceeded low density lipoprotein clearance by 1.5- to 3-fold. The intimal clearances of plasma proteins, high density, low density, and very low density lipoproteins decreased linearly with the logarithm of the macromolecular diameter. This indicates that the arterial influx of three plasma lipoprotein fractions and of plasma proteins proceeds by similar mechanisms. Apparently the relative intimal clearances of lipoproteins are more dependent on their size relative to pores or vesicular diameters at the plasma-artery interface than on specific interactions between lipoproteins and the arterial intimal surface

Uptake of low density lipoproteins by the hamster lung. Interactions with capillary endothelium

International Nuclear Information System (INIS)

Nistor, A.; Simionescu, M.

1986-01-01

The mechanism by which the circulating low density lipoproteins (LDL) contribute to the lung surfactant cholesterol was investigated by perfusing the hamster lung in situ with LDL either radiolabeled or coupled to gold, or both. Part of [ 125 I]-LDL and [ 3 H]-cholesterol LDL were taken up by a specific process which was time- and concentration-dependent and reached saturation within 20 to 30 min of perfusion. Competition experiments and removal of receptor-bound LDL by heparin suggested that about 50% of LDL uptake is receptor-independent. Experiments using double labeled LDL showed a preferential uptake of 3 H-cholesterol versus 125 I by the lung both in situ and in vivo. LDL-gold particles (LDL-Au), recirculated through the isolated lung, bound to the endothelial luminal plasma membrane and to features potentially involved in receptor-mediated endocytosis (coated pits, coated vesicles, lysosomelike structures) and in transcytosis (plasmalemmal vesicles). The results suggest that LDL uptake by the lung takes place by both receptor-mediated and receptor-independent mechanisms. Cholesterol may be in part transferred to the lung without the apoprotein moiety; the alveolar capillary endothelium appears to be the first monitor of this complex process

Lipoprotein Nanoplatform for Targeted Delivery of Diagnostic and Therapeutic Agents

Directory of Open Access Journals (Sweden)

Jerry D. Glickson

2008-03-01

Full Text Available Low-density lipoprotein (LDL provides a highly versatile natural nanoplatform for delivery of visible or near-infrared fluorescent optical and magnetic resonance imaging (MRI contrast agents and photodynamic therapy and chemotherapeutic agents to normal and neoplastic cells that overexpress low-density lipoprotein receptors (LDLRs. Extension to other lipoproteins ranging in diameter from about 10 nm (high-density lipoprotein [HDL] to over a micron (chylomicrons is feasible. Loading of contrast or therapeutic agents onto or into these particles has been achieved by protein loading (covalent attachment to protein side chains, surface loading (intercalation into the phospholipid monolayer, and core loading (extraction and reconstitution of the triglyceride/cholesterol ester core. Core and surface loading of LDL have been used for delivery of optical imaging agents to tumor cells in vivo and in culture. Surface loading was used for delivery of gadolinium-bis-stearylamide contrast agents for in vivo MRI detection in tumor-bearing mice. Chlorin and phthalocyanine near-infrared photodynamic therapy agents (≤ 400/LDL have been attached by core loading. Protein loading was used to reroute the LDL from its natural receptor (LDLR to folate receptors and could be used to target other receptors. A semisynthetic nanoparticle has been constructed by coating magnetite iron oxide nanoparticles with carboxylated cholesterol and overlaying a monolayer of phospholipid to which apolipoprotein A1 or E was adsorbed for targeting HDL or adsorbing synthetic amphipathic helical peptides ltargeting LDL or folate receptors. These particles can be used for in situ loading of magnetite into cells for MRI-monitored cell tracking or gene expression.

Increased oxidizability of low-density lipoproteins in hypothyroidism

NARCIS (Netherlands)

Diekman, T.; Demacker, P. N.; Kastelein, J. J.; Stalenhoef, A. F.; Wiersinga, W. M.

1998-01-01

Hypothyroidism leads to an increase of plasma low-density lipoprotein (LDL) cholesterol levels. Oxidation of LDL particles changes their intrinsic properties, thereby enhancing the development of atherosclerosis. T4 has three specific binding sites on apolipoprotein B; furthermore it inhibits LDL

The biological properties of iron oxide core high-density lipoprotein in experimental atherosclerosis

NARCIS (Netherlands)

Skajaa, Torjus; Cormode, David P.; Jarzyna, Peter A.; Delshad, Amanda; Blachford, Courtney; Barazza, Alessandra; Fisher, Edward A.; Gordon, Ronald E.; Fayad, Zahi A.; Mulder, Willem J. M.

2011-01-01

Lipoproteins are a family of plasma nanoparticles responsible for the transportation of lipids throughout the body. High-density lipoprotein (HDL), the smallest of the lipoprotein family, measures 7-13 nm in diameter and consists of a cholesteryl ester and triglyceride core that is covered with a

In vitro incorporation of radiolabeled cholesteryl esters into high and low density lipoproteins

International Nuclear Information System (INIS)

Terpstra, A.H.; Nicolosi, R.J.; Herbert, P.N.

1989-01-01

We have developed and validated a method for in vitro incorporation of radiolabeled cholesteryl esters into low density (LDL) and high density lipoproteins (HDL). Radiolabeled cholesteryl esters dissolved in absolute ethanol were mixed with LDL or HDL in the presence of lipoprotein-deficient serum (LPDS) as a source of core lipid transfer activity. The efficiency of incorporation was dependent on: (a) the core lipid transfer activity and quantity of LPDS, (b) the mass of added radiolabeled cholesteryl esters, (c) the length of incubation, and (d) the amount of acceptor lipoprotein cholesterol. The tracer incorporation was documented by repeat density gradient ultracentrifugation, agarose gel electrophoresis, and precipitation with heparin-MnCl2. The radiolabeling conditions did not affect the following properties of the lipoproteins: (1) chemical composition, (2) electrophoretic mobility on agarose gels, (3) hydrated density, (4) distribution of apoproteins on SDS gels, (5) plasma clearance rates, and (6) immunoprecipitability of HDL apoproteins A-I and A-II. Rat HDL containing radiolabeled cholesteryl esters incorporated in vitro had plasma disappearance rates identical to HDL radiolabeled in vivo

A role for the high-density lipoprotein receptor SR-B1 in synovial inflammation via serum amyloid-A.

LENUS (Irish Health Repository)

Mullan, Ronan Hugh

2012-02-01

Acute phase apoprotein Serum Amyloid A (A-SAA), which is strongly expressed in rheumatoid arthritis synovial membrane (RA SM), induces angiogenesis, adhesion molecule expression, and matrix metalloproteinase production through the G-coupled receptor FPRL-1. Here we report alternative signaling through the high-density lipoprotein receptor scavenger receptor-class B type 1 (SR-B1). Quantitative expression\\/localization of SR-B1 in RA SM, RA fibroblast-like cells (FLCs), and microvascular endothelial cells (ECs) was assessed by Western blotting and immunohistology\\/fluorescence. A-SAA-mediated effects were examined using a specific antibody against SR-B1 or amphipathic alpha-Helical Peptides (the SR-B1 antagonists L-37pA and D-37pA), in RA FLCs and ECs. Adhesion molecule expression and cytokine production were quantified using flow cytometry and ELISA. SR-B1 was strongly expressed in the RA SM lining layer and endothelial\\/perivascular regions compared with osteoarthritis SM or normal control synovium. Differential SR-B1 expression in RA FLC lines (n = 5) and ECs correlated closely with A-SAA, but not tumor necrosis factor alpha-induced intercellular adhesion molecule-1 upregulation. A-SAA-induced interleukin-6 and -8 production was inhibited in the presence of anti-SR-B1 in human microvascular endothelial cells and RA FLCs. Moreover, D-37pA and L-37pA inhibited A-SAA-induced vascular cell adhesion molecule-1 and intercellular adhesion molecule expression from ECs in a dose-dependent manner. As SR-B1 is expressed in RA synovial tissue and mediates A-SAA-induced pro-inflammatory pathways, a better understanding of A-SAA-mediated inflammatory pathways may lead to novel treatment strategies for RA.

Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor): Implications for the Efficacy of Evolocumab.

Science.gov (United States)

Thedrez, Aurélie; Blom, Dirk J; Ramin-Mangata, Stéphane; Blanchard, Valentin; Croyal, Mikaël; Chemello, Kévin; Nativel, Brice; Pichelin, Matthieu; Cariou, Bertrand; Bourane, Steeve; Tang, Lihua; Farnier, Michel; Raal, Frederick J; Lambert, Gilles

2018-03-01

Evolocumab, a PCSK9 (proprotein convertase subtilisin kexin type 9)-neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemic (HoFH) patients with reduced LDLR (low-density lipoprotein receptor) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition. Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial (Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders). Ten patients were true homozygotes (FH1/FH1) and 5 identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9-neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased, whereas rPCSK9 reduced LDLR expression. The PCSK9-neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, before and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C on evolocumab treatment. Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab. © 2017 American Heart Association

Role of Lipids in Spheroidal High Density Lipoproteins

NARCIS (Netherlands)

Vuorela, Timo; Catte, Andrea; Niemela, Perttu S.; Hall, Anette; Hyvonen, Marja T.; Marrink, Siewert-Jan; Karttunen, Mikko; Vattulainen, Ilpo

2010-01-01

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules

Role of lipids in spheroidal high density lipoproteins

NARCIS (Netherlands)

Vuorela, T.A.; Catte, A.; Niemelä, P.S.; Hall, A.; Hyvönen, M.T.; Marrink, S.J.; Karttunen, M.E.J.; Vattulainen, I.

2010-01-01

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules

Method of assessing a lipid-related health risk based on ion mobility analysis of lipoproteins

Science.gov (United States)

Benner, W. Henry; Krauss, Ronald M.; Blanche, Patricia J.

2010-12-14

A medical diagnostic method and instrumentation system for analyzing noncovalently bonded agglomerated biological particles is described. The method and system comprises: a method of preparation for the biological particles; an electrospray generator; an alpha particle radiation source; a differential mobility analyzer; a particle counter; and data acquisition and analysis means. The medical device is useful for the assessment of human diseases, such as cardiac disease risk and hyperlipidemia, by rapid quantitative analysis of lipoprotein fraction densities. Initially, purification procedures are described to reduce an initial blood sample to an analytical input to the instrument. The measured sizes from the analytical sample are correlated with densities, resulting in a spectrum of lipoprotein densities. The lipoprotein density distribution can then be used to characterize cardiac and other lipid-related health risks.

Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system.

Science.gov (United States)

Liu, Qiang; Zhang, Juan; Zerbinatti, Celina; Zhan, Yan; Kolber, Benedict J; Herz, Joachim; Muglia, Louis J; Bu, Guojun

2011-01-11

Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.

A high-density lipoprotein-mediated drug delivery system.

Science.gov (United States)

Mo, Zhong-Cheng; Ren, Kun; Liu, Xing; Tang, Zhen-Li; Yi, Guang-Hui

2016-11-15

High-density lipoprotein (HDL) is a comparatively dense and small lipoprotein that can carry lipids as a multifunctional aggregate in plasma. Several studies have shown that increasing the levels or improving the functionality of HDL is a promising target for treating a wide variety of diseases. Among lipoproteins, HDL particles possess unique physicochemical properties, including naturally synthesized physiological components, amphipathic apolipoproteins, lipid-loading and hydrophobic agent-incorporating characteristics, specific protein-protein interactions, heterogeneity, nanoparticles, and smaller size. Recently, the feasibility and superiority of using HDL particles as drug delivery vehicles have been of great interest. In this review, we summarize the structure, constituents, biogenesis, remodeling, and reconstitution of HDL drug delivery systems, focusing on their delivery capability, characteristics, applications, manufacturing, and drug-loading and drug-targeting characteristics. Finally, the future prospects are presented regarding the clinical application and challenges of using HDL as a pharmacodelivery carrier. Copyright © 2016 Elsevier B.V. All rights reserved.

Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response.

Science.gov (United States)

Naga, Mazen; Amin, Mona; Algendy, Dina; Elbadry, Ahmed; Fawzi, May; Foda, Ayman; Esmat, Serag; Sabry, Dina; Rashed, Laila; Gabal, Samia; Kamal, Manal

2015-10-21

To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients. Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non-responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR-based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases. There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30.6%, GG: 17.2%) (P A predominated in cases and controls over the A allele, and a statistically significant association with

In vitro production of beta-very low density lipoproteins and small, dense low density lipoproteins in mildly hypertriglyceridemic plasma: role of activities of lecithin:cholester acyltransferase, cholesterylester transfer proteins and lipoprotein lipase.

Science.gov (United States)

Chung, B H; Segrest, J P; Franklin, F

1998-12-01

As a model for the formation of beta-very low density lipoproteins (VLDL) and small, dense LDL by the intraplasma metabolic activities in vivo, lipoproteins in fresh plasma were interacted in vitro with endogenous lecithin:cholesterol acyltransferase (LCAT) and cholesterylester transfer proteins (CETP) and subsequently with purified lipoprotein lipase (LpL). The LCAT and CETP reactions in a mildly hypertriglyceridemic (HTG) plasma at 37 degrees C for 18 h resulted in (1) esterification of about 45% plasma unesterified cholesterol (UC), (2) a marked increase in cholesterylester (CE) (+129%) and a decrease in triglyceride (TG) (-45%) in VLDL, and (3) a marked increase of TG (+ 341%) with a small net decrease of CE (-3.6%) in LDL, causing a significant alteration in the TG/CE of VLDL (from 8.0 to 1.9) and of LDL (from 0.20 to 0.93). The LDL in LCAT and CETP-reacted plasma is larger and more buoyant than that in control plasma. In vitro lipolysis of control and LCAT and CETP-reacted plasma by LpL, which hydrolyzed >90% of VLDL-TG and about 50-60% of LDL-TG, converted most of VLDL in control plasma (>85%) but less than half (40%) of VLDL in LCAT and CETP-reacted plasma into the IDL-LDL density fraction and transformed the large, buoyant LDL in the LCAT and CETP-reacted plasma into particles smaller and denser than those in the control plasma. The remnants that accumulated in the VLDL density region of the postlipolysis LCAT and CETP-reacted plasma contained apo B-100 and E but little or no detectable apo Cs and consisted of particles having pre-beta and beta-electrophoretic mobilities. The inhibition of LCAT during incubation of plasma, which lessened the extent of alteration in VLDL and LDL core lipids, increased the extent of lipolytic removal of VLDL from the VLDL density region but lowered the extent of alteration in the size and density of LDL. The LCAT, CETP and/or LpL-mediated alterations in the density of LDL in normolipidemic fasting plasma were less pronounced

Novel Therapies Focused on the High-Density Lipoprotein Particle

NARCIS (Netherlands)

van Capelleveen, Julian C.; Brewer, H. Bryan; Kastelein, John J. P.; Hovingh, G. Kees

2014-01-01

Cardiovascular disease (CVD) remains a major burden for morbidity and mortality in the general population, despite current efficacious low-density lipoprotein-cholesterol-lowering therapies. Consequently, novel therapies are required to reduce this residual risk. Prospective epidemiological studies

Cholesteryl ester transfer activity in plasma measured by using solid-phase-bound high-density lipoprotein

International Nuclear Information System (INIS)

Sparks, D.L.; Frohlich, J.; Cullis, P.; Pritchard, P.H.

1987-01-01

We studied the ability of lipid-transfer factors in plasma to promote transfer, to endogenous lipoproteins, of [ 3 H]cholesteryl ester from high-density lipoprotein (HDL) covalently bound to Sepharose 4B beads. After incubation for 2 h at 37 degrees C, 12 to 14% of the [ 3 H]cholesteryl ester had been transferred to the lipoproteins of the plasma, in the proportions 57% to HDL and 43% to low- and very-low-density lipoproteins. This process was a function of the amount of plasma present and was stimulated by addition of partly purified lipid-transfer protein. Transfer also depended on the concentration of donor HDL but was independent of the amount of acceptor lipoprotein. This simple evaluation of cholesteryl ester transfer does not require removal of lipoproteins from the plasma before incubation

Essential oil of Pinus koraiensis leaves exerts antihyperlipidemic effects via up-regulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A: cholesterol acyltransferase.

Science.gov (United States)

Kim, Ji-Hyun; Lee, Hyo-Jung; Jeong, Soo-Jin; Lee, Min-Ho; Kim, Sung-Hoon

2012-09-01

Hyperlipidemia is an important factor to induce metabolic syndrome such as obesity, diabetes and cardiovascular diseases. Recently, some antihyperlipidemic agents from herbal medicines have been in the spotlight in the medical science field. Thus, the present study evaluated the antihyperlipidemic activities of the essential oil from the leaves of Pinus koraiensis SIEB (EOPK) that has been used as a folk remedy for heart disease. The reverse transcription polymerase chain reaction (RT-PCR) revealed that EOPK up-regulated low density lipoprotein receptor (LDLR) at the mRNA level as well as negatively suppressed the expression of sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT) involved in lipid metabolism in HepG2 cells. Also, western blotting showed that EOPK activated LDLR and attenuated the expression of FAS at the protein level in the cells. Consistently, EOPK significantly inhibited the level of human acylcoenzyme A: cholesterol acyltransferase (hACAT)1 and 2 and reduced the low-density lipoprotein (LDL) oxidation activity. Furthermore, chromatography-mass spectrometry (GC-MS) analysis showed that EOPK, an essential oil mixture, contained camphene (21.11%), d-limonene (21.01%), α-pinene (16.74%) and borneol (11.52%). Overall, the findings suggest that EOPK can be a potent pharmaceutical agent for the prevention and treatment of hyperlipidemia. Copyright © 2012 John Wiley & Sons, Ltd.

Should we change our lipid management strategies to focus on non-high-density lipoprotein cholesterol?

NARCIS (Netherlands)

Rana, Jamal S.; Boekholdt, S. Matthijs

2010-01-01

Purpose of review Despite aggressive low-density lipoprotein cholesterol lowering, patients continue to be at significant risk of cardiovascular events. Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the

Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system.

Directory of Open Access Journals (Sweden)

Qiang Liu

2011-01-01

Full Text Available Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.

Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression.

Science.gov (United States)

Mack, W J; Krauss, R M; Hodis, H N

1996-05-01

Accumulating evidence suggests that triglyceride-rich lipoproteins contribute to coronary artery disease. Using data from the Monitored Atherosclerosis Regression Study, an angiographic trial of middle-aged men and women randomized to lovastatin or placebo, we investigated relationships between lipoprotein subclasses and progression of coronary artery atherosclerosis. Coronary artery lesion progression was determined by quantitative coronary angiography in low-grade ( or = 50% diameter stenosis), and all coronary artery lesions in 220 baseline/2-year angiogram pairs. Analytical ultracentrifugation was used to measure lipoprotein masses that were statistically evaluated for treatment group differences and relationships to progression of coronary artery atherosclerosis. All low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL) masses were significantly lowered and all high density lipoprotein (HDL) masses were significantly raised with lovastatin therapy. The mass of smallest LDL (Svedberg flotation rate [Sf] 0 to 3), IDL (Sf 12 to 20), all VLDL subclasses (Sf 20 to 60, Sf 60 to 100, and Sf 100 to 400), and peak LDL flotation rate were significantly related to the progression of coronary artery lesions, specifically low-grade lesions. Greater baseline levels of HDL3, were related to a lower likelihood of coronary artery lesion progression. In multivariate analyses, small VLDL (Sf 20 to 60) and HDL3 mass were the most important correlates of coronary artery lesion progression. These results provide further evidence for the importance of triglyceride-rich lipoproteins in the progression of coronary artery disease. In addition, these results present new evidence for the possible protective role of HDL3 in the progression of coronary artery lesions. More specific information on coronary artery lesion progression may be obtained through the study of specific apolipoprotein B-containing lipoproteins.

Onset of lipoprotein-supported steroidogenesis in differentiating granulosa cells of rats: cellular events involved in mediating FSH-enhanced uptake of low-density lipoproteins

International Nuclear Information System (INIS)

Foster, J.D.

1987-01-01

Luteal cells use lipoproteins as the main source of cholesterol in steroidogenesis. However, little is known about the mechanisms underlying hormonal control of lipoprotein uptake. Thus, the authors tested the hypothesis that FSH and androgens regulate low density lipoprotein (LDL)-supported steroidogenesis in maturing granulosa cells by affecting receptor-mediated endocytosis of LDL at a cellular level. For this, immature ovarian granulosa cells were cultured with or without hormones, compactin (de novo synthesis inhibitor), or unlabeled or labeled ( 125 I or gold particles) LDL. Nonhormone-treated cultures produced little progestin; FSH and FSH/androstenedione stimulated steroid secretion. Progestin production by hormone-, but not nonhormone-, treated cultures was decreased by compactin, suggesting that de novo synthesis provided sterol for steroidogenesis. EM quantitation of cells exposed to gold-LDL at 37 0 C revealed that, compared to nonhormone-treated cells, FSH-treated cells (1) bound and internalized more gold-LDL, (2) had a smaller percentage of gold-LDL at their surfaces, (3) displayed a faster apparent rate of LDL internalization and delivery to lysosomes, and (4) contained more gold-labeled lysosomes. Data from biochemical studies in which 125 I-LDL was used supported the morphological findings. In conclusion, this study demonstrates that FSH has important effects at the cellular level on LDL uptake, which seem to underlie the striking increase in progestin production accompanying granulosa cell differentiation

The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated β-amyloid protein internalization in mouse brain.

Science.gov (United States)

Ma, Kai-Ge; Lv, Jia; Hu, Xiao-Dan; Shi, Li-Li; Chang, Ke-Wei; Chen, Xin-Lin; Qian, Yi-Hua; Yang, Wei-Na; Qu, Qiu-Min

2016-07-01

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular β-amyloid protein (Aβ) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control Aβ internalization may provide new insight for regulating Aβ levels. In the present study, the regulation of Aβ internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that Aβ1-42 were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. Aβ1-42-LRP1 complex was formed during Aβ1-42 internalization, and the p38 MAPK signaling pathway was activated by Aβ1-42 via LRP1. Aβ1-42 and LRP1 were co- localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in Aβ1-42 internalization in mouse brain. The results of this investigation demonstrated that Aβ1-42 induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of Aβ1-42. These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of Aβ1-42 internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chimeric RXFP1 and RXFP2 receptors highlight the similar mechanism of activation utilizing their N-terminal low density lipoprotein class A modules

Directory of Open Access Journals (Sweden)

Shoni eBruell

2013-11-01

Full Text Available Relaxin family peptide (RXFP receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low density lipoprotein type A (LDLa module which is necessary for receptor activation. The current hypothesis suggests that upon ligand binding the LDLa module interacts with the transmembrane (TM domain of a homodimer partner receptor to induce the active receptor conformations. We recently demonstrated that three residues in the N-terminus of the RXFP1 LDLa module are potentially involved in hydrophobic interactions with the receptor to drive activation. RXFP2 shares two out of three of the residues implicated, suggesting that the two LDLa modules could be interchanged without adversely affecting activity. However, in 2007 it was shown that a chimera consisting of the RXFP1 receptor with its LDLa swapped for that of RXFP2 did not signal. We noticed this construct also contained the RXFP2 region linking the LDLa to the leucine-rich repeats. We therefore constructed chimeric RXFP1 and RXFP2 receptors with their LDLa modules swapped immediately C-terminally to the final cysteine residue of the module, retaining the native linker. In addition, we exchanged the TM domains of the chimeras to explore if matching the LDLa module with the TM domain of its native receptor altered activity. All of the chimeras were expressed at the surface of HEK293T cells with ligand binding profiles similar to the wild-type receptors. Importantly, as predicted, ligand binding was able to induce cAMP based signalling. Chimeras of RXFP1 with the LDLa of RXFP2 demonstrated reduced H2 relaxin potency with the pairing of the RXFP2 TM with the RXFP2 LDLa necessary for full ligand efficacy. In contrast the ligand mediated potencies and efficacies on the RXFP2 chimeras were similar suggesting the RXFP1 LDLa module has similar efficacy on the RXFP2 TM domain. Our studies demonstrate the LDLa modules of RXFP1 and RXFP2 modulate receptor activation via a

CRISPR Correction of a Homozygous Low-Density Lipoprotein Receptor Mutation in Familial Hypercholesterolemia Induced Pluripotent Stem Cells.

Science.gov (United States)

Omer, Linda; Hudson, Elizabeth A; Zheng, Shirong; Hoying, James B; Shan, Yuan; Boyd, Nolan L

2017-11-01

Familial hypercholesterolemia (FH) is a hereditary disease primarily due to mutations in the low-density lipoprotein receptor (LDLR) that lead to elevated cholesterol and premature development of cardiovascular disease. Homozygous FH patients (HoFH) with two dysfunctional LDLR alleles are not as successfully treated with standard hypercholesterol therapies, and more aggressive therapeutic approaches to control cholesterol levels must be considered. Liver transplant can resolve HoFH, and hepatocyte transplantation has shown promising results in animals and humans. However, demand for donated livers and high-quality hepatocytes overwhelm the supply. Human pluripotent stem cells can differentiate to hepatocyte-like cells (HLCs) with the potential for experimental and clinical use. To be of future clinical use as autologous cells, LDLR genetic mutations in derived FH-HLCs need to be corrected. Genome editing technology clustered-regularly-interspaced-short-palindromic-repeats/CRISPR-associated 9 (CRISPR/Cas9) can repair pathologic genetic mutations in human induced pluripotent stem cells. We used CRISPR/Cas9 genome editing to permanently correct a 3-base pair homozygous deletion in LDLR exon 4 of patient-derived HoFH induced pluripotent stem cells. The genetic correction restored LDLR-mediated endocytosis in FH-HLCs and demonstrates the proof-of-principle that CRISPR-mediated genetic modification can be successfully used to normalize HoFH cholesterol metabolism deficiency at the cellular level.

Role of oxidized low-density lipoprotein in renal disease

NARCIS (Netherlands)

Heeringa, P; Tervaert, JWC

Accelerated atherosclerosis is often observed in patients with chronic renal failure. In the present review we summarize and discuss the recent literature on the pathogenic role of low-density lipoproteins modified by oxidative processes in atherosclerosis and the possible role in renal diseases.

Human Low Density Lipoprotein as a Vehicle of Atherosclerosis ...

African Journals Online (AJOL)

Low-density lipoproteins have been sufficiently established as an important precursor of atherosclerosis. The actual mechanism is still unclear, and the current technique of using radioisotopes has clinical limitation. However, the current study techniques or methods excellently elucidate the functional aspects of ...

In vivo transfer of cholesteryl ester from high and low density plasma lipoproteins into human aortic tissue

International Nuclear Information System (INIS)

Stender, S.; Hjelms, E.

1988-01-01

For the study of cholesteryl ester transfer from different plasma lipoproteins into human aortic tissue, patients scheduled for reconstructive aortic surgery were intravenously injected with autologous in vitro labeled lipoproteins 20 to 24 hours before aortic intima-media samples were obtained during the operation. The injectate contained high density lipoproteins (d greater than 1.063) labeled with 3H-cholesteryl ester and lipoproteins of lower density (d less than 1.063) labeled with 14C-cholesteryl ester or lipoproteins with the opposite labeling. In 16 aortic tissue samples (some with visible atherosclerosis) from 11 normocholesterolemic patients, the aortic influx of total cholesteryl ester was 1 to 50 nmol x cm-2 x day-1. Some 39% +/- 3% (mean +/- SEM) of the influx was derived from high density lipoproteins, which in plasma accounted for only 22% +/- 2% (mean +/- SEM) of the esterified cholesterol. The findings suggest that: 1) esterified cholesterol from the two lipoprotein fractions in plasma enter the aortic intima by the same mechanism, and 2) influx of cholesteryl ester from the smaller, high density lipoproteins is greater than influx from the larger, lower density lipoproteins considering their concentrations in plasma. In some patients, the cholesterol content in the intima-media tissue with no visible atherosclerosis corresponded to only a few months of continuous cholesteryl ester influx. This time is short considering the age of the patients and, therefore, indicates that removal of esterified cholesterol from the intima-media is of major importance in preventing cholesterol deposition in the arterial wall

Serum lipoproteins attenuate macrophage activation and Toll-Like Receptor stimulation by bacterial lipoproteins

Directory of Open Access Journals (Sweden)

James Richard W

2010-09-01

Full Text Available Abstract Background Chlamydia trachomatis was previously shown to express a lipoprotein, the macrophage infectivity potentiator (Mip, exposed at the bacterial surface, and able to stimulate human primary monocytes/macrophages through Toll Like Receptor (TLR2/TLR1/TLR6, and CD14. In PMA-differentiated THP-1 cells the proinflammatory activity of Mip was significantly higher in the absence than in the presence of serum. The present study aims to investigate the ability of different serum factors to attenuate Mip proinflammatory activity in PMA-differentiated THP-1 cells and in primary human differentiated macrophages. The study was also extend to another lipoprotein, the Borrelia burgdorferi outer surface protein (OspA. The proinflammatory activity was studied through Tumor Necrosis Factor alpha (TNF-α and Interleukin (IL-8 release. Finally, TLR1/2 human embryonic kidney-293 (HEK-293 transfected cells were used to test the ability of the serum factors to inhibit Mip and OspA proinflammatory activity. Results In the absence of any serum and in the presence of 10% delipidated FBS, production of Mip-induced TNF-α and IL-8 in PMA-differentiated THP-1 cells were similar whereas they were significantly decreased in the presence of 10% FBS suggesting an inhibiting role of lipids present in FBS. In the presence of 10% human serum, the concentrations of TNF-α and IL-8 were 2 to 5 times lower than in the presence of 10% FBS suggesting the presence of more potent inhibitor(s in human serum than in FBS. Similar results were obtained in primary human differentiated macrophages. Different lipid components of human serum were then tested (total lipoproteins, HDL, LDL, VLDL, triglyceride emulsion, apolipoprotein (apoA-I, B, E2, and E3. The most efficient inhibitors were LDL, VLDL, and apoB that reduced the mean concentration of TNF-α release in Mip-induced macrophages to 24, 20, and 2%, respectively (p Conclusions These results demonstrated the ability of

Early incorporation of cell-derived cholesterol into pre-beta-migrating high-density lipoprotein

International Nuclear Information System (INIS)

Castro, G.R.; Fielding, C.J.

1988-01-01

Cultures of human skin fibroblasts were labeled to high cholesterol specific activity with [ 3 H]cholesterol and incubated briefly (1-3 min) with normal human plasma. The plasma was fractionated by two-dimensional agarose-polyacrylamide gel electrophoresis and the early appearance of cholesterol label among plasma lipoproteins determined. A major part of the label at 1-min incubation was in a pre-beta-migrating apo A-I lipoprotein fraction with a molecular weight of ca. 70,000. Label was enriched about 30-fold in this fraction relative to its content of apo A-I (1-2% of total apo A-I). The proportion of label in this lipoprotein was strongly correlated with its concentration in plasma. Further incubation (2 min) in the presence of unlabeled cells demonstrated transfer of label from this fraction to a higher molecular weight pre-beta apo A-I species, to low-density lipoprotein, and to the alpha-migrating apo A-I that made up the bulk (96%) of total apo A-I in plasma. The data suggest that a significant part of cell-derived cholesterol is transferred specifically to a pre-beta-migrating lipoprotein A-I species as part of a cholesterol transport transfer sequence in plasma

Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss

NARCIS (Netherlands)

K.A.C. Berk (Kirsten); R. Vongpromek (Ranitha); M. Jiang (Meizi); W.J. Schneider (Wolfgang); R. Timman (Reinier); A.J.M. Verhoeven; H. Bujo (Hideaki); E.J.G. Sijbrands (Eric); M.T. Mulder (Monique)

2016-01-01

markdownabstract__Background and aims__ Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of

Alpha slow-moving high-density-lipoprotein subfraction in serum of a patient with radiation enteritis and peritoneal carcinosis

International Nuclear Information System (INIS)

Peynet, J.; Legrand, A.; Messing, B.; Thuillier, F.; Rousselet, F.

1989-01-01

An alpha slow-moving high-density-lipoprotein (HDL) subfraction was seen in a patient presenting with radiation enteritis and peritoneal carcinosis, who was given long-term cyclic parenteral nutrition. This subfraction, observed in addition to normal HDL, was precipitated with low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) by sodium phosphotungstate-magnesium chloride. The patient's serum lipoproteins were analyzed after fractionation by density gradient ultracentrifugation. The alpha slow-moving HDL floated in the ultracentrifugation subfractions with densities ranging from 1.028 to 1.084 kg/L, and their main apolipoproteins included apolipoprotein E in addition to apolipoprotein A-I. These HDL were larger than HDL2. The pathogenesis of this unusual HDL subfraction is hypothesized

Nonfasting Triglycerides, Low-Density Lipoprotein Cholesterol, and Heart Failure Risk

DEFF Research Database (Denmark)

Varbo, Anette; Nordestgaard, Børge G

2018-01-01

OBJECTIVE: The prevalence of heart failure is increasing in the aging population, and heart failure is a disease with large morbidity and mortality. There is, therefore, a need for identifying modifiable risk factors for prevention. We tested the hypothesis that high concentrations of nonfasting...... triglycerides and low-density lipoprotein cholesterol are associated with higher risk of heart failure in the general population. APPROACH AND RESULTS: We included 103 860 individuals from the Copenhagen General Population Study and 9694 from the Copenhagen City Heart Study in 2 prospective observational...... association studies. Nonfasting triglycerides and low-density lipoprotein cholesterol were measured at baseline. Individuals were followed for ≤23 years, during which time 3593 were diagnosed with heart failure. Hazard ratios were estimated using Cox proportional hazard regression models. In the Copenhagen...

High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.

Science.gov (United States)

Gordon, D J; Probstfield, J L; Garrison, R J; Neaton, J D; Castelli, W P; Knoke, J D; Jacobs, D R; Bangdiwala, S; Tyroler, H A

1989-01-01

The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was eliminated by covariance adjustment. Using the proportional hazards model and adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial (CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both randomized trials in middle-age high-risk men), only the control groups were analyzed. A 1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease mortality rates. The 95% confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably, and all contained the range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease mortality. When differences in analytic methodology were eliminated, a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.

Low-density lipoprotein cholesterol and risk of gallstone disease

DEFF Research Database (Denmark)

Stender, Stefan; Frikke-Schmidt, Ruth; Benn, Marianne

2013-01-01

Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone...

Antioxidant activity of high-density lipoprotein (HDL) using different ...

African Journals Online (AJOL)

HDL is a potent antioxidant in terms of inhibition of lipid peroxidation, ROS production and LDL oxidation. These may to some extent add to the antiatherogenic beyond reverse-cholesterol transport properties of HDL. Keywords: high-density lipoprotein; reverse cholesterol transport; apolipoprotein A1; antioxidant; in vitro.

Serum prolactin, leptin, lipids and lipoproteins levels during antipsychotics treatment in Parkinson's disease and related psychosis.

Science.gov (United States)

Rustembegovic, Avdo; Sofic, Emin; Wichart, Ildiko

2006-01-01

Weight gain is a common adverse effect associated with the use of most typical and atypical antipsychotic. Aim of this study was to investigate serum prolactin, leptin, cholesterol, triglyceride, lipoproteins, such high density lipoprotein (HDL), and low density lipoprotein (LDL) levels in patients with Parkinson's disease (PD)-related psychosis during long-term medication with atypical antipsychotic. The study population comprised 40 patients, who were divided into 4 groups: olanzapine (n=10), risperidone (n=10), seroquel (n=10) monotherapy, a group of 10 patients receiving only antiparkinson drugs and a control group of 8 healthy persons. The patients were evaluated at baseline and at the sixth and twelfth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), and fasting serum prolactin, leptin, lipids and lipoproteins levels. Treatment of patients with olanzapine caused marked increase of serum LDL, cholesterol, triglyceride, and leptin levels (prelationship between serum leptin, lipid levels and BMI. However, treatment of patients with seroquel did not cause changes in serum prolactin, leptin, lipids, and lipoproteins levels. Our results suggest that treatment of patients with PD-related psychosis with seroquel appears to have minimal influence on serum leptin, prolactin, lipids, lipoproteins and BMI compared with olanzapine and risperidone.

Identification of a point mutation in growth factor repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia

International Nuclear Information System (INIS)

Soutar, A.K.; Knight, B.L.; Patel, D.D.

1989-01-01

The coding region of the low density lipoprotein (LDL)-receptor gene from a patient (MM) with homozygous familial hypercholesterolemia (FH) has been sequenced from six overlapping 500-base-pair amplified fragments of the cDNA from cultured skin fibroblasts. Two separate single nucleotide base changes from the normal sequence were detected. The first involved substitution of guanine for adenine in the third position of the codon for amino acid residue Cys-27 and did not affect the protein sequence. The second mutation was substitution of thymine for cytosine in the DNA for the codon for amino acid residue 664, changing the codon from CCG (proline) to CTG (leucine) and introducing a new site for the restriction enzyme PstI. MM is a true homozygote with two identical genes, and the mutation cosegregated with clinically diagnosed FH in his family in which first cousin marriages occurred frequently. LDL receptors in MM's skin fibroblasts bind less LDL than normal and with reduced affinity. Thus this naturally occurring single point mutation affects both intracellular transport of the protein and ligand binding and occurs in growth factor-like repeat C, a region that has not previously been found to influence LDL binding

INHIBITION OF HUMAN LOW-DENSITY LIPOPROTEINS OXIDATION BY Hibiscus radiatus CUV. CALYCES EXTRACT

Directory of Open Access Journals (Sweden)

Hernawan Hernawan

2010-06-01

Full Text Available Hibiscus radiatus Cuv calyces extracts rich in polyphenols was screened for their potential to inhibit oxidation of human low-density lipoproteins-cholesterol (LDL-C in vitro. The inhibition of LDL-C oxidation (antioxidant activity was determined by measuring the formation of conjugated dienes and thiobarbituric acid reagent substances (TBARS. LDL-C oxidation was carried out in the presence of H. radiatus Cuv calyces extract (20 and 50 μM. CuSO4 (10 μM was used as the oxidation initiator and  butylated hydroxytoluene (BHT at 50 μM was used as standard antioxidant. The protective effect of H. radiatus Cuv. calyces extract toward human low-density lipoproteins, complex lipid system was  demonstrated by significant increase lag time (> 103 min, diminished of the propagation rate (44 %, and diminution of conjugated dienes formation 59.42 % (50 μM compared to control.   Keywords: antioxidant, conjugated dienes, Hibiscus radiatus Cuv, low-density lipoproteins-cholesterol

Increased fluidity and oxidation of malarial lipoproteins: relation with severity and induction of endothelial expression of adhesion molecules

Directory of Open Access Journals (Sweden)

Looareesuwan Sornchai

2004-06-01

Full Text Available Abstract Introduction Oxidative stress has been demonstrated in malaria. The potential oxidative modification of lipoproteins derived from malaria patients was studied. These oxidized lipids may have role in pathogenesis of malaria. Method The plasma lipid profile and existence of oxidized forms of very low density lipoprotein (VLDL, low density lipoprotein (LDL and high density lipoprotein (HDL were investigated in malaria (17 mild and 24 severe patients and 37 control subjects. Thiobarbituric acid reactive substances (TBARs, conjugated dienes, tryptophan fluorescence and fluidity of lipoproteins were determined as markers of oxidation. The biological effect of malarial lipoproteins was assessed by the expression of adhesion molecules on endothelial cells. Results Malarial lipoproteins had decreased cholesterol (except in VLDL and phospholipid. The triglyceride levels were unchanged. The cholesterol/phospholipid ratio of LDL was decreased in malaria, but increased in VLDL and HDL. TBARs and conjugate dienes were increased in malarial lipoproteins, while the tryptophan fluorescence was decreased. The fluidity of lipoproteins was increased in malaria. These indicated the presence of oxidized lipoproteins in malaria by which the degree of oxidation was correlated with severity. Of three lipoproteins from malarial patients, LDL displayed the most pronounced oxidative modification. In addition, oxidized LDL from malaria patients increased endothelial expression of adhesion molecules. Conclusion In malaria, the lipoproteins are oxidatively modified, and the degree of oxidation is related with severity. Oxidized LDL from malarial patients increases the endothelial expression of adhesion molecules. These suggest the role of oxidized lipoproteins, especially LDL, on the pathogenesis of disease.

Degradation of high density lipoprotein in cultured rat luteal cells

International Nuclear Information System (INIS)

Rajan, V.P.; Menon, K.M.J.

1986-01-01

In rat ovary luteal cells, degradation of high density lipoprotein (HDL) to tricholoracetic acid (TCA)-soluble products accounts for only a fraction of the HDL-derived cholesterol used for steroidogenesis. In this study the authors have investigated the fate of 125 I]HDL bound to cultured luteal cells using pulse-chase technique. Luteal cell cultures were pulse labeled with [ 125 I]HDL 3 and reincubated in the absence of HDL. By 24 h about 50% of the initallay bound radioactivity was released into the medium, of which 60-65% could be precipitated with 10% TCA. Gel filtration of the chase incubation medium on 10% agarose showed that the amount of TCA-soluble radioactivity was nearly completely accounted for by a sharp peak in the low molecular weight region which was identified as 96% monoiodotyrosine by paper chromatography. The TCA-precipitable radioactivity was nearly completely accounted for by a sharp peak in the low molecular weight region which was identified as 96% monoiodotyrosine by paper chromatography. The TCA-precipitable radioactivity eluted over a wide range of molecular weights (15,000-80,000), and there was very little intact HDL present. Electrophoresis of the chase medium showed that component of the TCA-precipitable portion had mobility similar to apo AI. Lysosomal inhibitors of receptor-mediated endocytosis had no effect on the composition or quantity of radioactivity released during chase incubation. The results show that HDL 3 binding to luteal cells is followed by complete degradation of the lipoprotein, although the TCA-soluble part does not reflect the extent of degradation

Comparison of different statin therapy to change low-density lipoprotein cholesterol and high-density lipoprotein cholesterol level in Korean patients with and without diabetes.

Science.gov (United States)

Khang, Ah Reum; Song, Young Shin; Kim, Kyoung Min; Moon, Jae Hoon; Lim, Soo; Park, Kyong Soo; Jang, Hak Chul; Choi, Sung Hee

2016-01-01

It is difficult to apply the proper intensity of statin for new treatment guidelines in clinical settings because of few data about the statin efficacy in Asians. We conducted a retrospective, observational study to estimate the percentage changes in lipid parameters and glucose induced by different statins. We analyzed 3854 patients including those with nondiabetes and diabetes treated at the outpatient clinic between 2003 and 2013 who were statin-naïve and maintained fixed-dose of statin for at least 18 months. Moderate- and low-intensity statin therapy was effective in reducing low-density lipoprotein cholesterol (LDL-C) to statin group. The effects of statins in elevating high-density lipoprotein cholesterol were similar in each statin groups, except the ezetimibe-simvastatin group (4.5 ± 2.1%) and high-dose atorvastatin groups (9.7 ± 3.3% and 8.7 ± 2.4% for 40 mg and 80 mg of atorvastatin/day, respectively). High-density lipoprotein cholesterol increased less and LDL-C decreased more in diabetes than in nondiabetes. There were no significant changes of fasting glucose after statin use in nondiabetic patients. Moderate- or low-intensity statin was effective enough in reaching National Cholesterol Education Program Adult Treatment Panel III LDL-C target goals in Koreans. Low-intensity statin showed around 30% LDL-C reduction from the baseline level in Koreans, which is comparable to moderate-intensity statin in new guideline. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Exposure to long wavelength ultraviolet radiation decreases processing of low density lipoprotein by cultured human fibroblasts

International Nuclear Information System (INIS)

Djavaheri-Mergny, M.; Santus, R.; Mora, L.; Maziere, J.C.; Faculte de Medecine Saint-Antoine, 75 -Paris; Maziere, C.; Auclair, M.; Dubertret, L.

1993-01-01

Exposure of MRC5 human fibroblasts to UVA radiation (365 nm) resulted in a dose-dependent decrease in low density lipoprotein (LDL) uptake and degradation by cells. Following a 25 J/cm 2 irradiation dose, about 45% and 70% reduction in 125 I-LDL uptake and degradation were observed, respectively. Under the same conditions, the 14 C-sucrose uptake was also decreased to about the same extent as LDL uptake. Cell pretreatment with the antioxidants vitamin E and vitamin C did not prevent the UVA-induced fall in LDL degradation. These results point to the possible effects of UVA radiation on receptor-mediated and nonspecific uptake of exogenous molecules. With special regard to the alterations in receptor-mediated processing of exogenous ligands, such a phenomenon could be of importance in UVA-induced skin degenerative processes. (Author)

Increased Antioxidant Quality Versus Lower Quantity Of High Density Lipoprotein In Benign Prostatic Hyperplasia

Directory of Open Access Journals (Sweden)

Aydin Ozgur

2015-10-01

Full Text Available Background: Oxidative stress may be involved in the pathogenesis of every human disease. To understand its possible role in benign prostatic hyperplasia (BPH, we measured the overall oxidative status of patients with BPH and the serum activity of the high density lipoprotein (HDL-related antioxidant enzymes paraoxonase 1 (PON1 and arylesterase (ARE.

A 90 minute soccer match decreases triglyceride and low density lipoprotein but not high-density lipoprotein and cholesterol levels

Directory of Open Access Journals (Sweden)

Nader - Rahnama

2009-11-01

Full Text Available

• BACKGROUND: The association between the lipid profiles level and the incidence and severity of coronary heart disease (CHD is very pronounced in epidemiological studies, and an inverse relation between physical fitness and the incidence of coronary heart disease has been observed in many studies. The aim of this study was to investigate the impact of a soccer match on lipid parameters of professional soccer players.
• METHODS: Twenty two professional soccer players participated in the study. Blood (10ml for determination of lipid profiles was obtained at rest and immediately after a 90 minute soccer match. Lipid parameters were measured using Boehringer Mannheim kits and Clinilab and BioMerieux analyser.
• RESULTS: The results of this study showed that the triglyceride was significantly higher before the match than afterwards (159.09 ± 58.2 vs. 88.63 ± 34.1 mg/dl, p < 0.001, whereas the low-density lipoprotein (LDL was lower before the match than after it (98.04 ± 28.9 vs. 112.31 ± 30.5 mg/dl. Moreover, there were no significant differences in cholesterol concentration (171.4 ± 30.28 mg/dl vs. 173.18 ± 32.75 mg/dl and high-density lipoprotein (HDL concentration (34.04 ± 5.58 mg/dl vs. 34.4 ± 4.6 mg/dl between before and after the match.
• CONCLUSIONS: Although the soccer competitive match has no favourable acute effect on lipid

• Biominetic High Density Lipoproteins for the Delivery of Therapeutic Oligonucleotides

  Science.gov (United States)

  Tripathy, Sushant

  Advances in nanotechnology have brought about novel inorganic and hybrid nanoparticles with unique physico-chemical properties that make them suitable for a broad range of applications---from nano-circuitry to drug delivery. A significant part of those advancements have led to ground-breaking discoveries that have changed the approaches to formulation of therapeutics against diseases, such as cancer. Now-a-days the focus does not lie solely on finding a candidate small-molecule therapeutic with minimal adverse effects, but researchers are looking up to nanoparticles to improve biodistribution and biocompatibility profile of clinically proven therapeutics. The plethora of conjugation chemistries offered by currently extant inorganic nanoparticles have, in recent years, led to great leaps in the field of biomimicry---a modality that promises high biocompatibility. Further, in the pursuit of highly specific therapeutic molecules, researchers have turned to silencing oligonucleotides and some have already brought together the strengths of nanoparticles and silencing oligonucleotides in search of an efficacious therapy for cancer with minimal adverse effects. This dissertation work focuses on such a biomimetic platform---a gold nanoparticle based high density lipoprotein biomimetic (HDL NP), for the delivery of therapeutic oligonucleotides. The first chapter of this body of work introduces the molecular target of the silencing oligonucleotides---VEGFR2, and its role in the progression of solid tumor cancers. The background information also covers important aspects of natural high density lipoproteins (HDL), especially their innate capacity to bind and deliver exogenous and endogenous silencing oligonucleotides to tissues that express their high affinity receptor SRB1. We subsequently describe the synthesis of the biomimetic HDL NP and its oligonucleotide conjugates, and establish their biocompatibility. Further on, experimental data demonstrate the efficacy of silencing

• Lipoprotein complex formation

  International Nuclear Information System (INIS)

  Musliner, T.A.; Krauss, R.M.

  1987-01-01

  Transfers of lipids and proteins between different lipoproteins are known to occur in the course of their metabolism. It is likely that these transfers take place during transient physical associations between lipoprotein particles, but the nature and chemical basis for such interactions are poorly understood. The fact that lipid and apolipoprotein movements are particularly prevalent during the intravascular lipolysis of triglyceride-rich lipoproteins suggested to us that lipolysis products accumulating on these particles might promote physical binding with other lipoproteins. To test this hypothesis, we studied interactions between very low-density, low density, and high-density lipoproteins in the setting of partial lipolysis by bovine milk lipoprotein lipase in the presence of limited unesterified fatty acid acceptor. 2 figs., 1 tab

• Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform

  NARCIS (Netherlands)

  Cormode, David P.; Skajaa, Torjus; van Schooneveld, Matti M.; Koole, Rolf; Jarzyna, Peter; Lobatto, Mark E.; Calcagno, Claudia; Barazza, Alessandra; Gordon, Ronald E.; Zanzonico, Pat; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

  2008-01-01

  High density lipoprotein (HDL) is an important natural nanoparticle that may be modified for biomedical imaging purposes. Here we developed a novel technique to create unique multimodality HDL mimicking nanoparticles by incorporation of gold, iron oxide, or quantum dot nanocrystals for computed

• Enhanced susceptibility of low-density lipoproteins to oxidation in coronary bypass patients with progression of atherosclerosis

  NARCIS (Netherlands)

  Rijke, Y.B. de; Verwey, H.F.; Vogelezang, C.J.M.; Velde, E.A. van der; Princen, H.M.G.; Laarse, A. van der; Bruschke, A.V.G.; Berkel, T.J.C. van

  1995-01-01

  Oxidation of low-density lipoprotein (LDL) may play a causal role in atherosclerosis. In this study we analyzed whether the severity of progression of coronary atherosclerosis is related to the susceptibility of LDL to oxidative modification. On the basis of repeated coronary angiography, 28

• Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice

  Directory of Open Access Journals (Sweden)

  Miyazawa Haruna

  2012-09-01

  Full Text Available Abstract Background Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9, which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models. Methods We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR gene and protein expression, as well as liver X receptors (Lxrs, inducible degrader of the LDLR (Idol, and sterol regulatory element binding transcription factor (Srebf2 gene expression, were examined in the liver. Results P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP2 (human homologue of Srebf2, whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection. Conclusions P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies

• Residues in the 5th module of the low-density lipoprotein receptor that bind apoE and apoB-100

  International Nuclear Information System (INIS)

  Kroon, P.A.; Zhang, H.-Y.; Smith, R.

  2000-01-01

  Full text: The low-density lipoprotein receptor (LDLR) binds and removes cholesterol-rich lipoproteins from the circulation. Its ligand-binding (LB) domain consists of seven cysteine-rich LB modules that bind apoB-100 and apoE. These modules fold into well-defined structures with three disulfide bonds, in the presence of Ca 2+ . The 5th module (LB5) is unique in that it is required to bind both apoB-100 and apoE. The aim of the current study was to map residues in human LB5 that are required for ligand binding. This was done by alanine mutagenesis of a series of residues that are conserved in human, mouse, rat and rabbit LB5 (E9, S14, E16, H19, S21, K31, and K33), but not in the other six modules. E37 (R37 in the rabbit) was included, since it has been previously hypothesized to play a role in binding. The variant LB5 modules were first produced as recombinant peptides, and subjected to oxidative folding to determine whether the mutations interfered with Ca 2+ '-dependent folding. Only the S14A and E16A mutations interfered significantly with folding, suggesting that S14 and E16 are required for the structural framework of LB5 and that their substitution in the LDLR may interfere with its folding. The native LDLR and E9A, H19A, S21A, K31A, K33A and E37A LDLRs were expressed in LDLR negative IdlA-7 CHO cells. Labeling with 125 I-lgG-C7 showed that all receptors were expressed on the cell surface. Binding of Dil-labeled LDL (Dil-LDL) and Dil-labeled DMPC, complexed with the N-terminal receptor-binding domain of apoE3 (Dil-E3), at 4 deg C, was used to assess receptor binding. Binding of Dil-E3 (0.1 μ/ml) to the H19A, S21A, K31A, K33A and E37A LDLRs was 65-92% of binding to the native LDLR. In contrast, the E9A LDLR only bound 3% of that of the native LDLR. The binding of Dil-LDL (0.5 Ag/ml) to the E9A LDLR was 23% of that of the native LDLR, while binding to the remaining variant LDLRs ranged from 44-70% of what of the native LDLR. We conclude that (i) E9 of LB5

• Aerosol preparation of intact lipoproteins

  Science.gov (United States)

  Benner, W Henry [Danville, CA; Krauss, Ronald M [Berkeley, CA; Blanche, Patricia J [Berkeley, CA

  2012-01-17

  A medical diagnostic method and instrumentation system for analyzing noncovalently bonded agglomerated biological particles is described. The method and system comprises: a method of preparation for the biological particles; an electrospray generator; an alpha particle radiation source; a differential mobility analyzer; a particle counter; and data acquisition and analysis means. The medical device is useful for the assessment of human diseases, such as cardiac disease risk and hyperlipidemia, by rapid quantitative analysis of lipoprotein fraction densities. Initially, purification procedures are described to reduce an initial blood sample to an analytical input to the instrument. The measured sizes from the analytical sample are correlated with densities, resulting in a spectrum of lipoprotein densities. The lipoprotein density distribution can then be used to characterize cardiac and other lipid-related health risks.

• Ion mobility analysis of lipoproteins

  Science.gov (United States)

  Benner, W. Henry; Krauss, Ronald M.; Blanche, Patricia J.

  2007-08-21

  A medical diagnostic method and instrumentation system for analyzing noncovalently bonded agglomerated biological particles is described. The method and system comprises: a method of preparation for the biological particles; an electrospray generator; an alpha particle radiation source; a differential mobility analyzer; a particle counter; and data acquisition and analysis means. The medical device is useful for the assessment of human diseases, such as cardiac disease risk and hyperlipidemia, by rapid quantitative analysis of lipoprotein fraction densities. Initially, purification procedures are described to reduce an initial blood sample to an analytical input to the instrument. The measured sizes from the analytical sample are correlated with densities, resulting in a spectrum of lipoprotein densities. The lipoprotein density distribution can then be used to characterize cardiac and other lipid-related health risks.

• Significance of oxidized low-density lipoprotein in body fluids as a marker related to diseased conditions.

  Science.gov (United States)

  Itabe, Hiroyuki; Kato, Rina; Sasabe, Naoko; Obama, Takashi; Yamamoto, Matsuo

  2018-03-06

  Oxidatively modified low-density lipoprotein (oxLDL) is known to be involved in various diseases, including cardiovascular diseases. The presence of oxLDL in the human circulatory system and in atherosclerotic lesions has been demonstrated using monoclonal antibodies. Studies have shown the significance of circulating oxLDL in various systemic diseases, including acute myocardial infarction and diabetic mellitus. Several different enzyme-linked immunosorbent assay (ELISA) procedures to measure oxLDL were utilized. Evidence has been accumulating that reveals changes in oxLDL levels under certain pathological conditions. Since oxLDL concentration tends to correlate with low-density lipoprotein (LDL)-cholesterol, the ratio of oxLDL and LDL rather than oxLDL concentration alone has been focused attention. In addition to circulating plasma, LDL and oxLDL are found in gingival crevicular fluid (GCF), where the ratio of oxLDL to LDL in GCF is much higher than in plasma. LDL and oxLDL levels in GCF show an increase in diabetic patients and periodontal patients, suggesting that GCF might be useful in examining systemic conditions. GCF oxLDL increased when the teeth were affected by periodontitis. It is likely that oxLDL levels in plasma and GCF could reflect oxidative stress and transfer efficacy in circulatory system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

NARCIS (Netherlands)

Bochem, Andrea E.; Holleboom, Adriaan G.; Romijn, Johannes A.; Hoekstra, Menno; Dallinga-Thie, Geesje M.; Motazacker, Mahdi M.; Hovingh, G. Kees; Kuivenhoven, Jan A.; Stroes, Erik S. G.

2013-01-01

Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To

Low-density lipoproteins cause atherosclerotic cardiovascular disease

DEFF Research Database (Denmark)

Ference, Brian A.; Ginsberg, Henry N.; Graham, Ian

2017-01-01

Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from...... proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from...

Structure of the LDL receptor extracellular domain at endosomalpH

Energy Technology Data Exchange (ETDEWEB)

Rudenko, Gabby; Henry, Lisa; Henderson, Keith; Ichtchenko,Konstantin; Brown, Michael S.; Goldstein, Joseph L.; Deisenhofer, Johann

2002-09-05

The structure of the low-density lipoprotein receptor extracellular portion has been determined. The document proposes a mechanism for the release of lipoprotein in the endosome. Without this release, the mechanism of receptor recycling cannot function.

The Hypocholesterolemic Effect of Germinated Brown Rice Involves the Upregulation of the Apolipoprotein A1 and Low-Density Lipoprotein Receptor Genes

Directory of Open Access Journals (Sweden)

Mustapha Umar Imam

2013-01-01

Full Text Available Germinated brown rice (GBR is rich in bioactive compounds, which confer GBR with many functional properties. Evidence of its hypocholesterolemic effects is emerging, but the exact mechanisms of action and bioactive compounds involved have not been fully documented. Using type 2 diabetic rats, we studied the effects of white rice, GBR, and brown rice (BR on lipid profile and on the regulation of selected genes involved in cholesterol metabolism. Our results showed that the upregulation of apolipoprotein A1 and low-density lipoprotein receptor genes was involved in the hypocholesterolemic effects of GBR. Additionally, in vitro studies using HEPG2 cells showed that acylated steryl glycoside, gamma amino butyric acid, and oryzanol and phenolic extracts of GBR contribute to the nutrigenomic regulation of these genes. Transcriptional and nontranscriptional mechanisms are likely involved in the overall hypocholesterolemic effects of GBR suggesting that it may have an impact on the prevention and/or management of hypercholesterolemia due to a wide variety of metabolic perturbations. However, there is need to conduct long-term clinical trials to determine the clinical relevance of the hypocholesterolemic effects of GBR determined through animal studies.

PFOS induced lipid metabolism disturbances in BALB/c mice through inhibition of low density lipoproteins excretion

Science.gov (United States)

Wang, Ling; Wang, Yu; Liang, Yong; Li, Jia; Liu, Yuchen; Zhang, Jie; Zhang, Aiqian; Fu, Jianjie; Jiang, Guibin

2014-04-01

Male BALB/c mice fed with either a regular or high fat diet were exposed to 0, 5 or 20 mg/kg perfluorooctane sulfonate (PFOS) for 14 days. Increased body weight, serum glucose, cholesterol and lipoprotein levels were observed in mice given a high fat diet. However, all PFOS-treated mice got reduced levels of serum lipid and lipoprotein. Decreasing liver glycogen content was also observed, accompanied by reduced serum glucose levels. Histological and ultrastructural examination detected more lipid droplets accumulated in hepatocytes after PFOS exposure. Moreover, transcripitonal activity of lipid metabolism related genes suggests that PFOS toxicity is probably unrelevant to PPARα's transcription. The present study demonstrates a lipid disturbance caused by PFOS and thus point to its role in inhibiting the secretion and normal function of low density lipoproteins.

Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice

NARCIS (Netherlands)

M.J. van Haperen (Rien); A. van Tol (Arie); P. Vermeulen; M. Jauhiainen; T. van Gent (Teus); P.M. van den Berg (Paul); S. Ehnholm (Sonja); A.W.M. van der Kamp (Arthur); M.P.G. de Crom (Rini); F.G. Grosveld (Frank)

2000-01-01

textabstractPlasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoprotein particles and alters high density lipoprotein (HDL) subfraction patterns in vitro, but its physiological function is poorly understood. Transgenic mice that overexpress

Effects of hormones on lipids and lipoproteins

Energy Technology Data Exchange (ETDEWEB)

Krauss, R.M.

1991-12-01

Levels of plasma lipids and lipoproteins are strong predictors for the development of atherosclerotic cardiovascular disease in postmenopausal women. In women, as in men, numerous factors contribute to variations in plasma lipoproteins that may affect cardiovascular disease risk. These include age, dietary components, adiposity, genetic traits, and hormonal changes. Each of these factors may operate to varying degrees in determining changes in plasma lipoprotein profiles accompanying menopause- Cross-sectional and longitudinal studies have suggested increases in levels of cholesterol, low density lipoproteins (LDL) and triglyceride-rich lipoproteins associated with menopause. High density lipoproteins (HDL), which are higher in women than men and are thought to contribute to relative protection of premenopausal women from cardiovascular disease, remain relatively constant in the years following menopause, although small, and perhaps transient reductions in the HDL{sub 2} subfraction have been reported in relation to reduced estradiol level following menopause. Despite these associations, it has been difficult to determine the role of endogenous hormones in influencing the plasma lipoproteins of postmenopausal women. In principle, the effects of hormone replacement should act to reverse any alterations in lipoprotein metabolism that are due to postmenopausal hormone changes. While there may be beneficial effects on lipoproteins, hormone treatment does not restore a premenopausal lipoprotein profile. Furthermore, it is not dear to what extent exogenous hormone-induced lipoprotein changes contribute to the reduced incidence of cardiovascular disease with hormone replacement therapy.

Serum oxidized low density lipoprotein levels in preeclamptic and normotensive pregnants.

Science.gov (United States)

Kozan, A; Yildirmak, S Turkmen; Mihmanli, V; Ayabakan, H; Cicek, Y G; Kalaslioglu, V; Doean, S; Cebeci, H Cerci

2015-01-01

BACKGROUNDS/AIM: The aim of the study was to determine serum lipids and oxidized low density lipoprotein (ox-LDL) levels in preeclamptic pregnants and compare with those of normotensives. Ox-LDL levels were determined by enzyme linked immunosorbent assay (ELISA); total cholesterol, hight density lipoprotein (HDL)-cholesterol and triglyceride levels were measured by enzymatic colorimetric assay in 26 normotensive and 27 preeclamptic pregnants. LDL and very low density lipoprotein (VLDL) cholesterol was calculated by Friedwald formula. Serum levels of Ox-LDL (U/L), total-cholesterol (mg/dL), HDL-cholesterol (mg/dL), LDL-cholesterol (mg/dL), triglyceride (mg/dL), and VLDL-cholesterol (mg/dL) in normotensive and preeclamptic pregnants were found as 130±60 and 133±69; 248±49 and 248±81; 67±14 and 61±16; 147±61 and 135±59; 207±76 and 256±87; 41±15 and 50±17, respectively. Mean values of Ox-LDL and other lipid parameters were higher than the upper limits of their reference ranges in both of groups. However no significant differences were found in Ox-LDL, total, HDL and LDL-cholesterol levels between two groups. However, the levels of triglyceride and VLDL-cholesterol were significantly higher in preeclampsia group. The present results suggest that the levels of serum Ox-LDL and other lipid parameters rise as a result of pregnancy rather than as a result of preeclampsia.

Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERα) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice

International Nuclear Information System (INIS)

Lee, Junga; Scheri, Richard C.; Zhang Yuan; Curtis, Lawrence R.

2008-01-01

Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [ 14 C]CD or [ 14 C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vitro reporter systems for human liver X receptors (LXRs) and activates those for human farnesoid X receptor (FXR), pregnane X receptor (PXR) and estrogen receptor α (ERα) in a concentration-dependent manner (0-50 μM). Consistent with human PXR activation in vitro, three days after a single dose of CD (15 mg/kg) hepatic microsomal CYP3A11 protein increases in C57BL/6 mice. CD decreases hepatic CH ester content without altering total CH concentration. Apolipoprotein A-I (apoA-I) contents of hepatic lipoprotein-rich and microsomal fractions of CD-treated mice are higher than controls. There is a significant reduction in non-high density lipoprotein CH but not apolipoprotein B-48/100 (apoB-48/100) in plasma from CD-treated mice after a 4 h fast. At 14 days after 15 mg CD/kg apoA-I and apoB-100 proteins but not CYP3A11 protein in hepatic microsomes are similar to controls. This work indicates that altered CH homeostasis is a mode of OC insecticide action of relevance after a single dose. This at least partially explains altered CH tissue distribution in CD-pretreated mice

Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces cardiac fibroblast proliferation by suppressing GATA Binding Protein 4

Energy Technology Data Exchange (ETDEWEB)

Liu, Bin; Liu, Ning-Ning; Liu, Wei-Hua; Zhang, Shuang-Wei; Zhang, Jing-Zhi; Li, Ai-Qun [Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Guangzhou Institute of Cardiovascular Disease, Guangzhou (China); Liu, Shi-Ming, E-mail: gzliushiming@126.com [Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Guangzhou Institute of Cardiovascular Disease, Guangzhou (China)

2016-07-08

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and GATA Binding Protein 4 (GATA4) are important for the growth of cardiac fibroblasts (CFs). When deregulated, LOX-1 and GATA4 can cause cardiac remodeling. In the present study, we found novel evidence that GATA4 was required for the LOX-1 regulation of CF proliferation. The inhibition of LOX-1 by RNA interference LOX-1 lentivirus resulted in the loss of PI3K/Akt activation and GATA4 protein expression. The overexpression of LOX-1 by lentivirus rescued CF proliferation, PI3K/Akt activation, and GATA4 protein expression. Moreover, GATA4 overexpression enhanced CF proliferation with LOX-1 inhibition. We also found that the inhibition of PI3K/Akt activation by LY294002, a PI3K inhibitor, reduced cell proliferation and protein level of GATA4. In summary, GATA4 may play an important role in the LOX-1 and PI3K/Akt regulation of CF proliferation. -- Highlights: •GATA4 is regulated by LOX-1 signaling in CFs. •GATA4 is involved in LOX-1 regulating CF proliferation. •GATA4 is regulated by PI3K/Akt signaling in CFs.

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

Directory of Open Access Journals (Sweden)

Rui M

2012-07-01

Full Text Available Mengjie Rui,1 Wei Guo,2 Qian Ding,2 Xiaohui Wei,2 Jianrong Xu,3 Yuhong Xu21School of Life Science and Biotechnology, 2School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China; 3Department of Radiology, Renji Hospital Affiliation with Medical School of Shanghai Jiao Tong University, Shanghai, People's Republic of ChinaBackground: Natural high-density lipoproteins (HDL possess important physiological functions to the transport of cholesterol from the peripheral tissues to the liver for metabolic degradation and excretion in the bile.Methods and results: In this work, we took advantage of this pathway and prepared two different gadolinium (Gd-DTPA-labeled cholesterol-containing recombinant HDL nanoparticles (Gd-chol-HDL and Gd-(chol2-HDL as liver-specific magnetic resonance imaging (MRI contrast agents. The reconstituted HDL nanoparticles had structural similarity to native HDL, and could be taken up by HepG2 cells via interaction with HDL receptors in vitro. In vivo MRI studies in rats after intravenous injections of 10 µmol gadolinium per kg of recombinant HDL nanoparticles indicated that both nanoparticles could provide signal enhancement in the liver and related organs. However, different T1-weighted image details suggested that they participated in different cholesterol metabolism and excretion pathways in the liver.Conclusion: Such information could be highly useful to differentiate functional changes as well as anatomic differences in the liver. These cholesterol-derived contrast agents and their recombinant HDL preparations may warrant further development as a new class of contrast agents for MRI of the liver and related organs.Keywords: magnetic resonance imaging, apolipoprotein, high-density lipoprotein, contrast agent, gadolinium, liver

Impact of hormonal contraception and weight loss on high-density lipoprotein cholesterol efflux and lipoprotein particles in women with polycystic ovary syndrome.

Science.gov (United States)

Dokras, Anuja; Playford, Martin; Kris-Etherton, Penny M; Kunselman, Allen R; Stetter, Christy M; Williams, Nancy I; Gnatuk, Carol L; Estes, Stephanie J; Sarwer, David B; Allison, Kelly C; Coutifaris, Christos; Mehta, Nehal; Legro, Richard S

2017-05-01

To study the effects of oral contraceptive pills (OCP), the first-line treatment for PCOS, on high-density lipoprotein cholesterol (HDL-C) function (reverse cholesterol efflux capacity) and lipoprotein particles measured using nuclear magnetic resonance spectroscopy in obese women. Secondary analysis of a randomized controlled trial (OWL-PCOS) of OCP or Lifestyle (intensive Lifestyle modification) or Combined (OCP + Lifestyle) treatment groups for 16 weeks. Eighty-seven overweight/obese women with PCOS at two academic centres. Change in HDL-C efflux capacity and lipoprotein particles. High-density lipoprotein cholesterol efflux capacity increased significantly at 16 weeks in the OCP group [0·11; 95% confidence interval (CI) 0·03, 0·18, P = 0·008] but not in the Lifestyle (P = 0·39) or Combined group (P = 0·18). After adjusting for HDL-C and TG levels, there was significant mean change in efflux in the Combined group (0·09; 95% CI 0·01, 0·15; P = 0·01). Change in HDL-C efflux correlated inversely with change in serum testosterone (r s = -0·21; P = 0·05). In contrast, OCP use induced an atherogenic low-density lipoprotein cholesterol (LDL-C) profile with increase in small (P = 0·006) and large LDL-particles (P = 0·002). Change in small LDL-particles correlated with change in serum testosterone (r s = -0·31, P = 0·009) and insulin sensitivity index (ISI; r s = -0·31, P = 0·02). Both Lifestyle and Combined groups did not show significant changes in the atherogenic LDL particles. Oral contraceptive pills use is associated with improved HDL-C function and a concomitant atherogenic LDL-C profile. Combination of a Lifestyle program with OCP use improved HDL-C function and mitigated adverse effects of OCP on lipoproteins. Our study provides evidence for use of OCP in overweight/obese women with PCOS when combined with Lifestyle changes. © 2017 John Wiley & Sons Ltd.

Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice.

Science.gov (United States)

Douglas, Robert M; Bowden, Karen; Pattison, Jennifer; Peterson, Alexander B; Juliano, Joseph; Dalton, Nancy D; Gu, Yusu; Alvarez, Erika; Imamura, Toshihiro; Peterson, Kirk L; Witztum, Joseph L; Haddad, Gabriel G; Li, Andrew C

2013-12-01

Patients with obstructive sleep apnea, who experience episodic hypoxia and hypercapnia during sleep, often demonstrate increased inflammation, oxidative stress, and dyslipidemia. We hypothesized that sleep apnea patients would be predisposed to the development of atherosclerosis. To dissect the mechanisms involved, we developed an animal model in mice whereby we expose mice to intermittent hypoxia/hypercapnia (IHH) in normobaric environments. Two- to three-month-old low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were fed a high-fat diet for 8 or 16 wk while being exposed to IHH for either 10 h/day or 24 h/day. Plasma lipid levels, pulmonary artery and aortic atherosclerotic lesions, and cardiac function were then assayed. Surprisingly, atherosclerosis in the aorta of IHH mice was similar compared with controls. However, in IHH mice, atherosclerosis was markedly increased in the trunk and proximal branches of the pulmonary artery of exposed mice; even though plasma cholesterol and triglycerides were lower than in controls. Hemodynamic analysis revealed that right ventricular maximum pressure and isovolumic relaxation constant were significantly increased in IHH exposed mice and left ventricular % fractional shortening was reduced. In conclusion, 1) Intermittent hypoxia/hypercapnia remarkably accelerated atherosclerotic lesions in the pulmonary artery of Ldlr(-/-) mice and 2) increased lesion formation in the pulmonary artery was associated with right and left ventricular dysfunction. These findings raise the possibility that patients with obstructive sleep apnea may be susceptible to atherosclerotic disease in the pulmonary vasculature, an observation that has not been previously recognized.

Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents

DEFF Research Database (Denmark)

Khetarpal, Sumeet A; Schjoldager, Katrine T; Christoffersen, Christina

2016-01-01

Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian mod...

Examination of the relation between periodontal health status and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen.

Science.gov (United States)

Wu, T; Trevisan, M; Genco, R J; Falkner, K L; Dorn, J P; Sempos, C T

2000-02-01

Using data from the Third National Health and Nutrition Examination Survey (1988-1994), the authors examined the relation between periodontal health and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen. A total of 10,146 participants were included in the analyses of cholesterol and C-reactive protein and 4,461 in the analyses of fibrinogen. Periodontal health indicators included the gingival bleeding index, calculus index, and periodontal disease status (defined by pocket depth and attachment loss). While cholesterol and fibrinogen were analyzed as continuous variables, C-reactive protein was dichotomized into two levels. The results show a significant relation between indicators of poor periodontal status and increased C-reactive protein and fibrinogen. The association between periodontal status and total cholesterol level is much weaker. No consistent association between periodontal status and high density lipoprotein cholesterol was detectable. Similar patterns of association were observed for participants aged 17-54 years and those 55 years and older. In conclusion, this study suggests that total cholesterol, C-reactive protein, and fibrinogen are possible intermediate factors that may link periodontal disease to elevated cardiovascular risk.

Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin

NARCIS (Netherlands)

Rodenburg, Jessica; Vissers, Maud N.; Wiegman, Albert; Miller, Elizabeth R.; Ridker, Paul M.; Witztum, Joseph L.; Kastelein, John J. P.; Tsimikas, Sotirios

2006-01-01

OBJECTIVES: To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin. BACKGROUND: Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The

Novel lipoprotein density profiling in healthy dogs of various breeds, healthy miniature schnauzers, and miniature schnauzers with hyperlipidemia

Science.gov (United States)

2013-01-01

Background Despite the importance of abnormalities in lipoprotein metabolism in clinical canine medicine, the fact that most previously used methods for lipoprotein profiling are rather laborious and time-consuming has been a major obstacle to the wide clinical application and use of lipoprotein profiling in this species. The aim of the present study was to assess the feasibility of a continuous lipoprotein density profile (CLPDP) generated within a bismuth sodium ethylenediaminetetraacetic acid (NaBiEDTA) density gradient to characterize and compare the lipoprotein profiles of healthy dogs of various breeds, healthy Miniature Schnauzers, and Miniature Schnauzers with primary hypertriacylglycerolemia. A total of 35 healthy dogs of various breeds with serum triacylglycerol (TAG) and cholesterol concentrations within their respective reference intervals were selected for use as a reference population. Thirty-one Miniature Schnauzers with serum TAG and cholesterol concentrations within their respective reference intervals and 31 Miniature Schnauzers with hypertriacylglyceridemia were also included in the study. Results The results suggest that CLPDP using NaBiEDTA provides unique diagnostic information in addition to measurements of serum TAG and cholesterol concentrations and that it is a useful screening method for dogs with suspected lipoprotein metabolism disorders. Using the detailed and continuous density distribution information provided by the CLPDP, important differences in lipoprotein profiles can be detected even among dogs that have serum TAG and cholesterol concentrations within the reference interval. Miniature Schnauzers with serum TAG and cholesterol concentrations within the reference interval had significantly different lipoprotein profiles than dogs of various other breeds. In addition, it was further established that specific lipoprotein fractions are associated with hypertriacylglyceridemia in Miniature Schnauzers. Conclusions The results of the

Social Inclusion Predicts Lower Blood Glucose and Low-Density Lipoproteins in Healthy Adults.

Science.gov (United States)

Floyd, Kory; Veksler, Alice E; McEwan, Bree; Hesse, Colin; Boren, Justin P; Dinsmore, Dana R; Pavlich, Corey A

2017-08-01

Loneliness has been shown to have direct effects on one's personal well-being. Specifically, a greater feeling of loneliness is associated with negative mental health outcomes, negative health behaviors, and an increased likelihood of premature mortality. Using the neuroendocrine hypothesis, we expected social inclusion to predict decreases in both blood glucose levels and low-density lipoproteins (LDLs) and increases in high-density lipoproteins (HDLs). Fifty-two healthy adults provided self-report data for social inclusion and blood samples for hematological tests. Results indicated that higher social inclusion predicted lower levels of blood glucose and LDL, but had no effect on HDL. Implications for theory and practice are discussed.

Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy.

Science.gov (United States)

Zabirnyk, Olga; Liu, Wei; Khalil, Shadi; Sharma, Anit; Phang, James M

2010-03-01

Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible for the latter. To elucidate the role of POX in oxLDL-mediated cytotoxicity, we knocked down POX via small interfering RNA and found that this (i) further reduced viability of cancer cells treated with oxLDL; (ii) decreased oxLDL-associated reactive oxygen species generation; (iii) decreased autophagy measured via beclin-1 protein level and light-chain 3 protein (LC3)-I into LC3-II conversion. Using POX-expressing cell model, we established that single POX overexpression was sufficient to activate autophagy. Thus, it led to autophagosomes accumulation and increased conversion of LC3-I into LC3-II. Moreover, beclin-1 gene expression was directly dependent on POX catalytic activity, namely the generation of POX-dependent superoxide. We conclude that POX is critical in the cellular response to the noxious effects of oxLDL by activating protective autophagy.

The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout

International Nuclear Information System (INIS)

Prindiville, John S.; Mennigen, Jan A.; Zamora, Jake M.; Moon, Thomas W.; Weber, Jean-Michel

2011-01-01

Gemfibrozil (GEM) is a fibrate drug consistently found in effluents from sewage treatment plants. This study characterizes the pharmacological effects of GEM on the plasma lipoproteins of rainbow trout (Oncorhynchus mykiss). Our goals were to quantify the impact of the drug on: 1) lipid constituents of lipoproteins (phospholipids (PL), triacylglycerol (TAG), and cholesterol), 2) lipoprotein classes (high, low and very low density lipoproteins), and 3) fatty acid composition of lipoproteins. Potential mechanisms of GEM action were investigated by measuring lipoprotein lipase activity (LPL) and the hepatic gene expression of LPL and of the peroxisome proliferator-activated receptor (PPAR) α, β, and γ isoforms. GEM treatment resulted in decreased plasma lipoprotein levels (- 29%) and a reduced size of all lipoprotein classes (lower PL:TAG ratios). However, the increase in HDL-cholesterol elicited by GEM in humans failed to be observed in trout. Therefore, HDL-cholesterol cannot be used to assess the impact of the drug on fish. GEM also modified lipoprotein composition by reducing the abundance of long-chain n-3 fatty acids, thereby potentially reducing the nutritional quality of exposed fish. The relative gene expression of LPL was increased, but the activity of the enzyme was not, and we found no evidence for the activation of PPAR pathways. The depressing effects of GEM on fish lipoproteins demonstrated here may be a concern in view of the widespread presence of fibrates in aquatic environments. Work is needed to test whether exposure to environmental concentrations of these drugs jeopardizes the capacity of fish for reproduction, temperature acclimation or migratory behaviors.

Purification of a sarcoplasmic reticulum protein that binds Ca2+ and plasma lipoproteins

International Nuclear Information System (INIS)

Hofmann, S.L.; Brown, M.S.; Lee, E.; Pathak, R.K.; Anderson, R.G.; Goldstein, J.L.

1989-01-01

A protein in the sarcoplasmic reticulum of rabbit skeletal and cardiac muscle was identified because of its ability to bind 125I-labeled low density lipoprotein (LDL) with high affinity after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This protein, referred to as the 165-kDa protein, is restricted to striated muscle. It was not detected in 14 other tissues, including several that contain smooth muscle, but it appears in rat L6 myoblasts when they differentiate into myocytes. Immunofluorescence and immunoelectron microscopic studies revealed that the protein is present throughout the sarcoplasmic reticulum and the terminal cisternae. It binds 45Ca2+ on nitrocellulose blots and stains metachromatically with Stains-all, a cationic dye that stains Ca2+-binding proteins. It does not appear to be a glycoprotein, and it appears slightly larger than the 160-kDa glycoprotein previously described in sarcoplasmic reticulum. The 165-kDa protein binds LDL, beta-migrating very low density lipoprotein, and a cholesterol-induced high density lipoprotein particle that contains apoprotein E as its sole apoprotein with much higher affinity than it binds high density lipoprotein. The protein is stable to boiling and to treatment with sodium dodecyl sulfate, but it becomes sensitive to these treatments when its cystine residues are reduced and alkylated. The protein was purified 1300-fold to apparent homogeneity from rabbit skeletal muscle membranes. It differs from the cell surface LDL receptor in that (1) its apparent molecular weight is not changed by reduction and alkylation; (2) it is present in Watanabe-heritable hyperlipidemic rabbits, which lack functional LDL receptors; (3) binding of lipoproteins is not inhibited by EDTA; and (4) it is located within the lumen of the sarcoplasmic reticulum where it has no access to plasma lipoproteins

Kandungan kolesterol, High Density Lipoprotein (HDL dan low density lipopro-tein (LDL darah burung puyuh dengan pemberian aditif cair buah naga merah

Directory of Open Access Journals (Sweden)

Khabib Arrosichin

2016-04-01

Full Text Available The study aims to determine, assess and evaluate the content of cholesterol, high density lipoprotein (HDL and Low Density Lipoprotein (LDL blood quail which were treated with liquid additive red dragon fruit. Materials used in the study were 200 female quails aged 14 days with an average weight of 13.61 ± 0.49 g. Ration composed by metabolizable energy content of ± 3000 kcal/kg and ± 20% of crude protein. The study consisted of 4 treatments and 5 replications. The treatments were (T0: without addition of liquid red dragon fruit (control; T1: addition of 5 ml liquid red dragon fruit twice a day; T2: addition of 5 ml liquid red dragon fruit once a day and T3: addition of 5 ml liquid red dragon fruit once in every two days. Blood sampling was performed in EDTA tube at the end of the study. Analysis of samples was carried out in health laboratory Semarang. The results were analyzed using analysis of variance (ANOVA. The study showed that the addition of liquid red dragon fruit additive had no significant effect (P> 0.05 on cholesterol, HDL and LDL of quil’s blood. Keywords: Quail, cholesterol; HDL, LDL, and red dragon fruit

High-density lipoprotein is a potential growth factor for adrenocortical cells

International Nuclear Information System (INIS)

Murao, Koji; Imachi, Hitomi; Cao, Wenming; Yu, Xiao; Li, Junhua; Yoshida, Kazuya; Ahmed, Rania A.M.; Matsumoto, Kensuke; Nishiuchi, Takamasa; Wong, Norman C.W.; Ishida, Toshihiko

2006-01-01

The entry of cholesterol contained within high-density lipoprotein (HDL) into adrenocortical cells is mediated by a human homologue of SR-BI, CD36, and LIMPII Analogous-1 (CLA-1) and thus augmenting their growth. To address the role of CLA-1, we created a mutant mCLA that lacked the C-terminal tail. HDL CE selective uptake by cells carrying the mCLA-1 receptor was fully active and equivalent to those transfected with full-length CLA-1 (fCLA-1). Expression of mCLA inhibited the proliferation of an adrenocortical cell line and the incorporation of [ 3 H]thymidine into the cells. This effect was sensitive to wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). Our transcriptional studies revealed that the inhibitory action of mCLA required the transcriptional factor AP-1 and the effect of HDL on AP-1 activation was also abrogated by wortmannin. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for adrenocortical tumor

Structural and metabolic heterogeneity of plasma low density lipoproteins in nonhuman primates

International Nuclear Information System (INIS)

Marzetta, C.A.

1986-01-01

To test the hypothesis that a variety of precursor particles secreted by the liver could result in heterogeneity of LDL products in plasma, the metabolic fate of selected radiolabeled hepatic lipoproteins evaluated was determined in vivo. The hepatic lipoproteins evaluated were isolated from liver perfusate and were triglyceride-rich VLDL (d < 1.006 or d < 1.017) and phospholipid-rich LDL (1.017 < d < 1.049 or 1.030 < d < 1.063). Radiolabeled autologous plasma LDL were injected into recipient animals together with the radiolabeled hepatic lipoproteins. Density gradient ultracentrifugation and gel filtration were used to characterize the distribution of radiolabeled lipoproteins in the plasma at selected times after injection. A variety of hepatic lipoproteins were precursors to lipoproteins that resembled plasma LDL. Between 22 to 80% of the injected dose of radiolabeled hepatic lipoprotein apo B-100 was converted to plasma LDL-like particles, regardless of the type of hepatic lipoprotein injected. A kinetic model was generated to describe the metabolic behavior of hepatic VLDL-derived and plasma LDL-derived apo B-100 radioactivity. Both models required multiple metabolic pools to fit the data. Hepatic VLDL-derived apo B-100 radioactivity was metabolized rapidly into various kinds of LDL subfractions. This rapid conversion of hepatic VLDL apo B-100 to LDL apo B-100 may be analogous to the portion of plasma VLDL that gets converted to LDL without passing through the delipidation cascade that has been described in humans and has been termed direct LDL production

The Human Pathogen Streptococcus pyogenes Releases Lipoproteins as Lipoprotein-rich Membrane Vesicles.

Science.gov (United States)

Biagini, Massimiliano; Garibaldi, Manuela; Aprea, Susanna; Pezzicoli, Alfredo; Doro, Francesco; Becherelli, Marco; Taddei, Anna Rita; Tani, Chiara; Tavarini, Simona; Mora, Marirosa; Teti, Giuseppe; D'Oro, Ugo; Nuti, Sandra; Soriani, Marco; Margarit, Immaculada; Rappuoli, Rino; Grandi, Guido; Norais, Nathalie

2015-08-01

Bacterial lipoproteins are attractive vaccine candidates because they represent a major class of cell surface-exposed proteins in many bacteria and are considered as potential pathogen-associated molecular patterns sensed by Toll-like receptors with built-in adjuvanticity. Although Gram-negative lipoproteins have been extensively characterized, little is known about Gram-positive lipoproteins. We isolated from Streptococcus pyogenes a large amount of lipoproteins organized in vesicles. These vesicles were obtained by weakening the bacterial cell wall with a sublethal concentration of penicillin. Lipid and proteomic analysis of the vesicles revealed that they were enriched in phosphatidylglycerol and almost exclusively composed of lipoproteins. In association with lipoproteins, a few hypothetical proteins, penicillin-binding proteins, and several members of the ExPortal, a membrane microdomain responsible for the maturation of secreted proteins, were identified. The typical lipidic moiety was apparently not necessary for lipoprotein insertion in the vesicle bilayer because they were also recovered from the isogenic diacylglyceryl transferase deletion mutant. The vesicles were not able to activate specific Toll-like receptor 2, indicating that lipoproteins organized in these vesicular structures do not act as pathogen-associated molecular patterns. In light of these findings, we propose to name these new structures Lipoprotein-rich Membrane Vesicles. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Changes of very low-density lipoprotein concentration in hepatic blood from cows with fasting-induced hepatic lipidosis.

Science.gov (United States)

Oikawa, Shin; Mizunuma, Yuko; Iwasaki, Yukari; Tharwat, Mohamed

2010-10-01

The purpose of this study was to evaluate changes of very low-density lipoprotein (VLDL) components in hepatic blood (HB) from 5 nonlactating nonpregnant cows fasted from days 0 to 3 and subsequently refed to day 10 and, in addition, to assess those of other lipoproteins. Increased phospholipid concentrations in each lipoprotein after the start of fasting suggested their availability for the surface lipids of lipoproteins. Although the VLDL-triglyceride (TG) concentration in HB from all cows increased on day 1, the value on day 4 became similar to that on day 0. However, the concentration on day 10 was significantly increased. In all cows, the decreased ratio of the VLDL-TG concentration in HB to the non-esterified fatty acids (NEFA) concentration in portal blood (PB) on day 4 appeared to reflect relatively decreased secretion of TG as VLDL by NEFA excessively mobilized to the liver via PB. The markedly increased ratio on day 10 was considered to contribute to the improvement of hepatic lipidosis.

Radiolabelled lipoproteins and method for making same

International Nuclear Information System (INIS)

Lees, R.S.

1987-01-01

A method is described for detecting accumulation of low density lipoproteins in an arterial wall, the method comprising the steps of A. preparing a technetium-99m-labelled low density lipoprotein in a solution having a pH between 8 and 9; B. injecting the labelled low density lipoprotein into the vascular system of a patient; C. subsequently viewing the patient's vascular system with extracorporeally-located detecting means capable of detecting the labelled low density lipoprotein; D. determining from the detecting means the locations of the labelled density lipoproteins; and E. quantifying concentrations of the labelled low density lipoproteins at the locations to determine the accumulation of the lipoproteins

Histamine H3 receptor density is negatively correlated with neural activity related to working memory in humans.

Science.gov (United States)

Ito, Takehito; Kimura, Yasuyuki; Seki, Chie; Ichise, Masanori; Yokokawa, Keita; Kawamura, Kazunori; Takahashi, Hidehiko; Higuchi, Makoto; Zhang, Ming-Rong; Suhara, Tetsuya; Yamada, Makiko

2018-06-14

The histamine H 3 receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H 3 receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H 3 receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H 3 receptors in the prefrontal cortex. Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H 3 receptor density was measured with the selective PET radioligand [ 11 C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H 3 receptors in this region. Higher neural activity of working memory was associated with lower H 3 receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H 3 receptors in working memory and indicates the potential of H 3 receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.

Modification of low-density lipoprotein by different radioiodination methods

International Nuclear Information System (INIS)

Sobal, G.; Resch, U.; Sinzinger, H.

2004-01-01

Scintigraphic imaging of radiolabeled low-density lipoproteins (LDL) is an interesting tool for the understanding of its role in pathomechanism of atherosclerosis. Metabolism of native LDL shows quite different pattern and kinetics as compared to that of modified LDL which is not mediated by classical LDL-receptor and accumulates in atherosclerotic lesions to form lipid-laden foam cells. Therefore we were interested whether radiolabelling of LDL induces structural modifications. We performed the iodine labeling of LDL for scintigraphic imaging of atherosclerosis by three different methods: chloramine-T (A), iodine monochloride (B) and iodogen (C). The highest radiolabelling yield of 125 I was obtained by the iodogen method (75.44±13.52%) and the lowest (49.01±12.74%) by iodine monochloride. Chloramine T showed a labeling yield of 62.82±6.17%. The stability of the tracer was very high with all the methods, persisting up to 6 h (98.83±1.2% - 91.38±4.7%, 15 min vs 6 h after labeling). For the first time we not only investigated the influence of radiolabelling on relative electrophoretic mobility (REM), but also various oxidation parameters such as baseline dienes (BD), thiobarbituric acid reactive substances (TBARS), endogenous peroxides (POX) and oxidation resistance in the copper-mediated oxidation system (expressed as lag-time) were measured. Furthermore, oxidation- derived fragmentation of the lipoproteins was examined with SDS-PAGE electrophoresis. Data are expressed as % change compared to native LDL before radiolabeling. BD were reduced by 32% using the method (A), but increased by 33% and 47% with the monochloride (B) and iodogen method (C), respectively. The effect on lag-time was comparable for all the three methods, ranging from 25 to 36% reduction in lag-time. TBARS were strongly increased 5-7 fold by all the methods. REM was changed by all three methods. While by methods A and C we have found a moderate increase in REM by 1.75 and 2.0 fold

LDL Receptor-Related Protein-1 (LRP1 Regulates Cholesterol Accumulation in Macrophages.

Directory of Open Access Journals (Sweden)

Anna P Lillis

Full Text Available Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the in vivo contribution of the LDL receptor-related protein 1 (LRP1 to this process is not known [corrected]. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR-deficient background (macLRP1-/-. After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp+/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis.

Direct effects of fatty meals and adiposity on oxidised low-density lipoprotein.

Science.gov (United States)

Laguna-Camacho, Antonio; Alonso-Barreto, Arely S; Mendieta-Zerón, Hugo

2015-01-01

High-fat intake and high adiposity contribute to hyperlipaemia. In a hyperlipaemic state, lipoproteins infiltrate arterial wall where they are modified and cause an immune response characteristic of atherosclerosis. A small fraction of modified lipoproteins including oxidised low-density lipoprotein (ox-LDL) returns to circulation. The present study tracked high-fat meals during four weeks as to find effects of sustained frequency change on adiposity and ox-LDL. The findings indicated that changes in frequency of consumption of high-fat eating episodes correlated directly with changes in adiposity and ox-LDL. Hence the number of fatty meals consumed by people with overweight or obesity in few weeks could affect the atherogenic process. Copyright © 2015 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase

International Nuclear Information System (INIS)

Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M.; Brown, Robert J.

2014-01-01

Highlights: • Lipoprotein hydrolysis products were produced by lipoprotein lipase. • Hydrolysis products lowers expression of macrophage cholesterol transporters. • Hydrolysis products reduces expression of select nuclear receptors. • Fatty acid products lowers cholesterol transporters and select nuclear receptors. • Fatty acid products reduces cholesterol efflux from macrophages. - Abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL

Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase

Energy Technology Data Exchange (ETDEWEB)

Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M.; Brown, Robert J., E-mail: rbrown@mun.ca

2014-09-05

Highlights: • Lipoprotein hydrolysis products were produced by lipoprotein lipase. • Hydrolysis products lowers expression of macrophage cholesterol transporters. • Hydrolysis products reduces expression of select nuclear receptors. • Fatty acid products lowers cholesterol transporters and select nuclear receptors. • Fatty acid products reduces cholesterol efflux from macrophages. - Abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.

Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice

Science.gov (United States)

Bowden, Karen; Pattison, Jennifer; Peterson, Alexander B.; Juliano, Joseph; Dalton, Nancy D.; Gu, Yusu; Alvarez, Erika; Imamura, Toshihiro; Peterson, Kirk L.; Witztum, Joseph L.; Haddad, Gabriel G.; Li, Andrew C.

2013-01-01

Patients with obstructive sleep apnea, who experience episodic hypoxia and hypercapnia during sleep, often demonstrate increased inflammation, oxidative stress, and dyslipidemia. We hypothesized that sleep apnea patients would be predisposed to the development of atherosclerosis. To dissect the mechanisms involved, we developed an animal model in mice whereby we expose mice to intermittent hypoxia/hypercapnia (IHH) in normobaric environments. Two- to three-month-old low-density lipoprotein receptor deficient (Ldlr−/−) mice were fed a high-fat diet for 8 or 16 wk while being exposed to IHH for either 10 h/day or 24 h/day. Plasma lipid levels, pulmonary artery and aortic atherosclerotic lesions, and cardiac function were then assayed. Surprisingly, atherosclerosis in the aorta of IHH mice was similar compared with controls. However, in IHH mice, atherosclerosis was markedly increased in the trunk and proximal branches of the pulmonary artery of exposed mice; even though plasma cholesterol and triglycerides were lower than in controls. Hemodynamic analysis revealed that right ventricular maximum pressure and isovolumic relaxation constant were significantly increased in IHH exposed mice and left ventricular % fractional shortening was reduced. In conclusion, 1) Intermittent hypoxia/hypercapnia remarkably accelerated atherosclerotic lesions in the pulmonary artery of Ldlr−/− mice and 2) increased lesion formation in the pulmonary artery was associated with right and left ventricular dysfunction. These findings raise the possibility that patients with obstructive sleep apnea may be susceptible to atherosclerotic disease in the pulmonary vasculature, an observation that has not been previously recognized. PMID:23990245

Withdrawal from high-carbohydrate, high-saturated-fat diet changes saturated fat distribution and improves hepatic low-density-lipoprotein receptor expression to ameliorate metabolic syndrome in rats.

Science.gov (United States)

Hazarika, Ankita; Kalita, Himadri; Kalita, Mohan Chandra; Devi, Rajlakshmi

2017-06-01

The "lipid hypothesis" determined that saturated fatty acid (SFA) raises low-density lipoprotein cholesterol, thereby increasing the risk for metabolic syndrome (MetS). The aim of this study was to investigate the effect of subchronic withdrawal from a high-carbohydrate, high-saturated fat (HCHF) diet during MetS with reference to changes in deleterious SFA (C12:0, lauric acid; C14:0, myristic acid; C16:0, palmitic acid; C18:0, stearic acid) distribution in liver, white adipose tissue (WAT), and feces. MetS induced by prolonged feeding of an HCHF diet in Wistar albino rat is used as a model of human MetS. The MetS-induced rats were withdrawn from the HCHF diet and changed to a basal diet for final 4 wk of the total experimental duration of 16 wk. SFA distribution in target tissues and hepatic low-density lipoprotein receptor (LDLr) expression were analyzed. Analyses of changes in SFA concentration of target tissues indicate that C16:0 and C18:0 reduced in WAT and liver after withdrawal of the HCHF diet. There was a significant (P < 0.001) decrease in fecal C12:0 with HCHF feeding, which significantly (P < 0.01) increased after withdrawal of this diet. Also, an improvement in expression of hepatic LDLr was observed after withdrawal of HCHF diet. The prolonged consumption of an HCHF diet leads to increased SFA accumulation in liver and WAT, decreased SFA excretion, and reduced hepatic LDLr expression during MetS, which is prominently reversed after subchronic withdrawal of the HCHF diet. This can contribute to better understanding of the metabolic fate of dietary SFA during MetS and may apply to the potential reversal of complications by the simple approach of nutritional modification. Copyright © 2017 Elsevier Inc. All rights reserved.

High triglycerides and low high-density lipoprotein cholesterol lipid profile in rheumatoid arthritis: A potential link among inflammation, oxidative status, and dysfunctional high-density lipoprotein.

Science.gov (United States)

Rodríguez-Carrio, Javier; Alperi-López, Mercedes; López, Patricia; López-Mejías, Raquel; Alonso-Castro, Sara; Abal, Francisco; Ballina-García, Francisco J; González-Gay, Miguel Á; Suárez, Ana

The interactions between inflammation and lipid profile in rheumatoid arthritis (RA) are poorly understood. The lipid profile study in RA has been biased toward lipoprotein levels, whereas those of triglycerides (TGs) and lipoprotein functionality have been underestimated. Since recent findings suggest a role for TG and TG-rich lipoproteins (TRL) on inflammation, we aimed to evaluate a combined lipid profile characterized by high TG and low high-density lipoprotein cholesterol levels (TG high HDL low ) in RA. Lipid profiles were analyzed in 113 RA patients, 113 healthy controls, and 27 dyslipemic subjects. Levels of inflammatory mediators, paraoxonase-1 (PON1) activity, and total antioxidant capacity were quantified in serum. PON1-rs662 status was evaluated by real-time polymerase chain reaction. The TG high HDL low profile was detected in 29/113 RA patients. Although no differences in prevalence compared with healthy controls or dyslipemic subjects were observed, this profile was associated with increased tumor necrosis factor α (P = .004), monocyte chemotactic protein (P = .004), interferon-gamma-inducible protein-10 (P = .018), and leptin (P < .001) serum levels in RA, where decreased PON1 activity and total antioxidant capacity were found. TG high HDL low prevalence was lower among anti-TNFα-treated patients (P = .004). When RA patients were stratified by PON1-rs662 status, these associations remained in the low-activity genotype (QQ). Finally, a poor clinical response on TNFα blockade was related to an increasing prevalence of the TG high HDL low profile over treatment (P = .021) and higher TRL levels at baseline (P = .042). The TG high HDL low profile is associated with systemic inflammation, decreased PON1 activity, and poor clinical outcome on TNFα blockade in RA, suggesting a role of TRL and HDL dysfunction as the missing link between inflammation and lipid profile. Copyright © 2017 National Lipid Association. Published by Elsevier Inc

Plasma Cholesteryl Ester Transfer, But Not Cholesterol Esterification, Is Related to Lipoprotein-Associated Phospholipase A(2) : Possible Contribution to an Atherogenic Lipoprotein Profile

NARCIS (Netherlands)

Dullaart, Robin P. F.; Constantinides, Alexander; Perton, Frank G.; van Leeuwen, Jeroen J. J.; van Pelt, Joost L.; de Vries, Rindert; van Tol, Arie

Context: Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) predicts incident cardiovascular disease and is associated preferentially with negatively charged apolipoprotein B-containing lipoproteins. The plasma cholesteryl ester transfer (CET) process, which contributes to low high-density

Lipoprotein profile, lipoprotein-associated phospholipase A2 and cardiovascular risk in hemodialysis patients.

Science.gov (United States)

Rolla, Roberta; De Mauri, Andreana; Valsesia, Ambra; Vidali, Matteo; Chiarinotti, Doriana; Bellomo, Giorgio

2015-12-01

Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis patients; the increased risk of cardiovascular disease is due to accelerated atherosclerosis, inflammation and impaired lipoprotein metabolism. We aimed to evaluate lipoprotein-associated phospholipase A2 (Lp-PLA2) and some pro-inflammatory aspects of the lipoprotein profile in dialyzed patients in order to evaluate the relationship with the accelerated atherosclerosis and vascular accidents. In 102 dialysis patients and 40 non-uremic controls, we investigated the lipoprotein plasma profile, high sensitivity C-reactive protein (CRP), ceruloplasmin and serum amyloid A protein (SAA), and followed patients for 1 year to analyze the risk of acute cardiovascular events. Total cholesterol, low-density lipoprotein and high-density lipoprotein plasma levels were significantly lower in uremic patients than controls, whereas CRP, SAA, ceruloplasmin, Lp-PLA2 and their ratio with apolipoprotein A1 were significantly higher. Patients with Lp-PLA2 levels >194 nmol/min/ml had more acute cardiovascular events than patients with lower values. Our results show that in dialysis subjects: (1) low-density lipoproteins show a more atherogenic phenotype than in the general population; (2) high-density lipoproteins are less anti-inflammatory; (3) Lp-PLA2 could potentially be used to evaluate cardiovascular risk.

Kinetics of incorporation/redistribution of photosensitizer hypericin to/from high-density lipoproteins

Czech Academy of Sciences Publication Activity Database

Joniova, J.; Buriánková, L.; Búzová, Diana; Miškovský, P.; Jančura, D.

2014-01-01

Roč. 475, 1-2 (2014), s. 578-584 ISSN 0378-5173 Institutional support: RVO:67179843 Keywords : aggregation * drug delivery * fluorescence * high- and low- density lipoproteins * Hypericin Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 3.650, year: 2014

Effect of I125 on oxidation behavior of lipoprotein subpopulations

International Nuclear Information System (INIS)

Majtenyi, S.

2002-07-01

Lipoproteins play a central role in lipid metabolism. They serve as a transport vehicle for cholesterol and triglycerides keeping them in plasma in solution. Lipoproteins are characterized by the content of specific apoproteins and differences in the hydrated density ranges. Moreover, they are distinguished by electrophoretic mobility and other characteristics as high and low-density lipoproteins, respectively lipoprotein (a). More specifically, HDL is classified into HDL 2 and HDL 3 . In atherogenesis, lipoproteins are considered to play a key-role. Oxidatively modified LDL is selectively taken up via scavenger receptors of the macrophage-monocyte system. These cells are transformed into foam cells promoting atherogenesis in vessels in the subendothelial space. Oxidized HDL essentially appears to loose its protective effects on LDL and its beneficial function in reverse cholesterol transport. Thus, it turns proatherogenic. The effects various species of free radicals exert on lipoproteins are the reason for this oxidative modification. Thyroid function also influences lipoproteins in a complex manner. Based on their hydrated density ranges, lipoprotein subpopulations were fractionated and isolated via isopycnic density gradient ultracentrifugation. After investigation of the general oxidation behavior, initiated by addition of CuSO 4 to the isolated samples of HDL 3 , HDL 2 , LDL and Lp(a), the influence of different activities of radioiodine-125 on the kinetics of the formation of conjugated dienes was assessed. This was achieved by coincubation of plasma with I 125 . The spectrophotometrical measurement of the concentration of conjugated dienes in the course of CuSO 4 -induced lipid peroxidation leads to measurable changes in absorption at 234 nm. These changes in absorption over time result in a characteristically shaped curve graphically plotted. The shape of these curves mirrors different indicators of lipid peroxidation. Therefrom lag time, maximal

Comparison of human plasma low- and high-density lipoproteins as substrates for lecithin: cholesterol acyltransferase.

Science.gov (United States)

Barter, P J; Hopkins, G J; Gorjatschko, L

1984-01-17

A recent observation that lecithin: cholesterol acyltransferase (EC 2.3.1.43) interacts with both low-density lipoproteins (LDL) and high-density lipoproteins (HDL) in human plasma is in apparent conflict with an earlier finding that the purified enzyme, while highly reactive with isolated HDL, was only minimally reactive with LDL. There is evidence, however, that lecithin: cholesterol acyltransferase may exist physiologically as a component of a complex with other proteins and that studies with the isolated enzyme may therefore provide misleading results. Consequently, interactions of the enzyme with isolated human lipoproteins have been re-examined in incubations containing lecithin: cholesterol acyltransferase as a component of human lipoprotein-free plasma in which a physiologically active complex of the enzyme with other proteins may have been preserved. In this system there was a ready esterification of the free cholesterol associated with both LDL and HDL-subfraction 3 (HDL3) in reactions that obeyed typical enzyme-saturation kinetics. For a given preparation of lipoprotein-free plasma the Vmax values with LDL and with HDL3 were virtually identical. The apparent Km for free cholesterol associated with HDL3 was 5.6 X 10(-5) M, while for that associated with LDL it was 4.1 X 10(-4) M. This implied that, in terms of free cholesterol concentration, the affinity of HDL3 for lecithin: cholesterol acyltransferase was about 7-times greater than that of LDL. When expressed in terms of lipoprotein particle concentration, however, it was apparent that the affinity of LDL for the enzyme was considerably greater than that of HDL3. When the lipoprotein fractions were equated in terms of lipoprotein surface area, the apparent affinities of the two fractions for the enzyme were found to be comparable.

Ascorbic acid protects lipids in human plasma and low-density lipoprotein against oxidative damage

Energy Technology Data Exchange (ETDEWEB)

Frei, B. (Department of Nutrition, Harvard School of Public Health, Boston, MA (Unites States))

1991-12-01

The authors exposed human blood plasma and low-density lipoprotein (LDL) to many different oxidative challenges and followed the temporal consumption of endogenous antioxidants in relation to the initiation of oxidative damage. Under all types of oxidizing conditions, ascorbic acid completely protects lipids in plasma and LDL against detectable peroxidative damage as assessed by a specific and highly sensitive assay for lipid peroxidation. Ascorbic acid proved to be superior to the other water-soluble plasma antioxidants bilirubin, uric acid, and protein thiols as well as to the lipoprotein-associated antioxidants alpha-tocopherol, ubiquinol-10, lycopene, and beta-carotene. Although these antioxidants can lower the rate of detectable lipid peroxidation, they are not able to prevent its initiation. Only ascorbic acid is reactive enough to effectively intercept oxidants in the aqueous phase before they can attack and cause detectable oxidative damage to lipids.

Investigations on the transport and metabolism of high density lipoprotein cholesteryl esters in African green monkeys

International Nuclear Information System (INIS)

Sorci-Thomas, M.G.

1984-01-01

The metabolic fate of circulating high density lipoprotein cholesteryl esters was studied in African green monkeys to determine the significance of the lipid transfer reaction on the catabolism of lipoprotein cholesteryl esters. A method of doubly labeling both moieties of lipoprotein cholesteryl esters with [ 3 He]cholesteryl oleate and cholesteryl [ 14 C]oleate was developed for the purpose of studying plasma cholesteryl ester metabolism in vivo. In these studies the total plasma [ 3 He]cholesterol turnover resulted in production rates, which ranged from 10-17 mg/kg day, similar to previously reported values in African green monkeys and in normal lipoproteinemic humans. In contrast to the production rates calculated from the decay of plasma 3 He-radioactivity, the production rates calculated from lipoproteins labeled with cholesteryl [ 14 C]oleate were approximately 2-3 times greater. In addition to these studies, a plasma cholesteryl ester transacylation activity was demonstrated in vitro when HDL containing doubly labeled cholesteryl esters were incubated with fresh plasma. These results demonstrated that high density lipoprotein cholesteryl esters undergo transacylation in vitro, resulting in release and reesterification of free [ 3 H]cholesterol

UVB-induced photoperoxidation of lipids of human low and high density lipoproteins. A possible role of tryptophan residues

International Nuclear Information System (INIS)

Salmon, S.; Maziere, J.C.; Santus, R.; Bouchemal, N.; Morliere, P.

1990-01-01

Ultraviolet radiation of the UVB region readily destroys tryptophan (Trp) residues of low (LDL) and high (HDL) density lipoproteins. The photooxidation of tryptophan residues is accompanied by peroxidation of low and high density lipoproteins unsaturated fatty acids, as measured by thiobarbituric acid assay. Moreover, low and high density lipoproteins are natural carriers of vitamin E and carotenoids. These two antioxidants are also rapidly bleached by UVB. The UVA radiation promotes neither tryptophan residue destruction nor lipid photoperoxidation. The redox cycling Cu 2+ ions considerably increase lipid photoperoxidation. The synergistic action of photo and auto (Cu 2+ -induced) peroxidation induces marked post-irradiation modifications of apolipoproteins as illustrated by degradation of most tryptophan residues after overnight incubation in the dark of pre-irradiated samples. (author)

The effect of insulin deficiency on the plasma clearance and exchange of high-density-lipoprotein phosphatidylcholine in rats.

Science.gov (United States)

Martins, I J; Redgrave, T G

1992-01-01

Triolein/cholesteryl oleate/cholesterol/phosphatidylcholine emulsions designed to model the lipid composition of chylomicrons were injected intravenously into control and streptozotocin-treated insulin-deficient rats. As previously described for lymph chylomicrons, the emulsion triolein was hydrolysed and phosphatidylcholine was transferred to the plasma high-density lipoproteins (HDL). This mechanism was used to introduce a phospholipid label into HDL in vivo. The subsequent clearance of phospholipid radioactivity from the plasma of insulin-deficient rats was significantly slower than in controls (P less than 0.025). Plasma clearance was similarly slower in insulin-deficient rats after injection of HDL that was previously labelled with radioactive phospholipids. After injection, the phospholipid label redistributed rapidly between the large-particle fraction of plasma lipoproteins (very-low- and low-density lipoproteins), and the lighter and heavier fractions of HDL. Compared with control rats, in insulin-deficient rats less of the phospholipid label was distributed to the lighter HDL fraction and more to the heavier HDL fraction, and this difference was not due to changes in activity of lecithin: cholesterol acyltransferase or in the apparent activity of phospholipid transfer protein. In insulin-deficient rats the changes in HDL phospholipid clearance and exchange appeared to be secondary to the associated hypertriglyceridaemia and the related changes in distribution of phospholipids between classes of plasma lipoproteins. PMID:1536661

Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein

DEFF Research Database (Denmark)

Jacobsen, Linda; Madsen, P; Moestrup, S K

1996-01-01

the corresponding cDNA. The gene, designated SORL1, maps to chromosome 11q 23/24 and encodes a 2214-residue type 1 receptor containing a furin cleavage site immediately preceding the N terminus determined in the purified protein. The receptor, designated sorLA-1, has a short cytoplasmic tail containing a tyrosine...... density lipoprotein receptor gene family receptors, and 3) six tandemly arranged fibronectin type III repeats also found in certain neural adhesion proteins. sorLA-1 may therefore be classified as a hybrid receptor. Northern blotting revealed specific mRNA transcripts in brain, spinal cord, and testis......The 39-40-kDa receptor-associated protein (RAP) binds to the members of the low density lipoprotein receptor gene family and functions as a specialized endoplasmic reticulum/Golgi chaperone. Using RAP affinity chromatography, we have purified a novel approximately 250-kDa brain protein and isolated...

Blood Lipoproteins under the Action of Exogenous Sex Steroids in the Postresuscitation Period

Directory of Open Access Journals (Sweden)

L. N. Shcherbakova

2011-01-01

Full Text Available Objective: to study the effect of reproductive hormones on the blood lipoprotein spectrum in the postresuscitation period after cardiac arrest. Materials and methods. Experiments were carried out on 66 mature albino rats of either sex weighing 200—250 g. Ten-minute cardiac arrest was induced by intrathoracic ligation of the vascular bundle. At 30 min after resuscitation, 49 animals were intramuscularly injected placebo and 17 animals were administered gyn-odian depot (Schering, Germany. The investigators measured the plasma concentrations of progesterone, 17-OH progesterone, androstenedione, dehydroepiandrosterone sulfate, testosterone, estradiol, and estriol, as well as the levels of triglycerides, total, and high-density lipoprotein (HDL, low-density lipoprotein (LDL, and very low-density lipoprotein (VLDL cholesterols. Blood was sampled on days 2 and 16 in the absence of therapy and on day 16 of sex steroid therapy. Results. By day 2 postresuscitation, the progesterone/estradiol ratio increased by approximately 1.8 times in males and females. Despite the fact that there were no changes in the concentrations of triglycerides, VLDL and HDL cholesterols in both males and females at that time, but the level of LDL cholesterol increased. Gender-related differences in the LDL spectrum by day 2 postresuscitation remained only in the levels of LDL cholesterol. Despite the normalization of progesterone levels, the concentrations of triglycerides and VLDL cholesterol decreased by day 16 of the postresuscitative period in the absence of therapy. There were no gender-related differences in the lipoprotein spectrum at this stage. The exogenous estradiol in combination with dehydroepiandrosterone caused a significant increase in the concentration of HLD cholesterol and a reduction in that of VLDL cholesterol in males and females both. Conclusion. Under gynodian action, the lipid spectrum was indicative of the exogenous estra-diol and

Use of the TLX ultracentrifuge for the isolation of different density lipoproteins and effects of freeze/thawing of human plasma before ultracentrifugation.

Science.gov (United States)

Charlton-Menys, Valentine; Chobotova, Jelena; Durrington, Paul N

2008-01-01

Isolation of different density lipoproteins by ultracentrifugation can require lengthy centrifugation times and freeze/thawing of plasma may influence recovery. We isolated a range of lipoproteins using a preparative ultracentrifuge and the TLX micro-ultracentrifuge and determined the effect of freeze/thawing of plasma beforehand. In fresh plasma, there was no significant difference in results for small-dense low-density lipoprotein apolipoprotein B (LDL apoB) (density >1.044 g/mL) or cholesterol at density >1.006 g/mL. Freeze/thawing had no effect on closely correlated results for small-dense LDL apoB (r=0.85; pTLX micro-ultracentrifuge is a reliable alternative to the preparative ultracentrifuge and freeze/thawing has only a small effect on small-dense LDL apoB or high-density lipoprotein cholesterol.

Nanotechnology for Synthetic High Density Lipoproteins

Science.gov (United States)

Luthi, Andrea J.; Patel, Pinal C.; Ko, Caroline H.; Mutharasan, R. Kannan; Mirkin, Chad A.; Thaxton, C. Shad

2014-01-01

Atherosclerosis is the disease mechanism responsible for coronary heart disease (CHD), the leading cause of death worldwide. One strategy to combat atherosclerosis is to increase the amount of circulating high density lipoproteins (HDL), which transport cholesterol from peripheral tissues to the liver for excretion. The process, known as reverse cholesterol transport, is thought to be one of the main reasons for the significant inverse correlation observed between HDL blood levels and the development of CHD. This article highlights the most common strategies for treating atherosclerosis using HDL. We further detail potential treatment opportunities that utilize nanotechnology to increase the amount of HDL in circulation. The synthesis of biomimetic HDL nanostructures that replicate the chemical and physical properties of natural HDL provides novel materials for investigating the structure-function relationships of HDL and for potential new therapeutics to combat CHD. PMID:21087901

Single-Particle Tracking of Human Lipoproteins.

Science.gov (United States)

de Messieres, Michel; Ng, Abby; Duarte, Cornelio J; Remaley, Alan T; Lee, Jennifer C

2016-01-05

Lipoproteins, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low density lipoprotein (VLDL), play a critical role in heart disease. Lipoproteins vary in size and shape as well as in their apolipoprotein content. Here, we developed a new experimental framework to study freely diffusing lipoproteins from human blood, allowing analysis of even the smallest HDL with a radius of 5 nm. In an easily constructed confinement chamber, individual HDL, LDL, and VLDL particles labeled with three distinct fluorophores were simultaneously tracked by wide-field fluorescence microscopy and their sizes were determined by their motion. This technique enables studies of individual lipoproteins in solution and allows characterization of the heterogeneous properties of lipoproteins which affect their biological function but are difficult to discern in bulk studies.

Drugs targeting high-density lipoprotein cholesterol for coronary artery disease management.

Science.gov (United States)

Katz, Pamela M; Leiter, Lawrence A

2012-01-01

Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Effects of stocking density on lipid deposition and expression of lipid-related genes in Amur sturgeon (Acipenser schrenckii).

Science.gov (United States)

Ren, Yuanyuan; Wen, Haishen; Li, Yun; Li, Jifang; He, Feng; Ni, Meng

2017-12-01

To investigate the correlation between lipid deposition variation and stocking density in Amur sturgeon (Acipenser schrenckii) and the possible physiological mechanism, fish were conducted in different stocking densities (LSD 5.5 kg/m 3 , MSD 8.0 kg/m 3 , and HSD 11.0 kg/m 3 ) for 70 days and then the growth index, lipid content, lipase activities, and the mRNA expressions of lipid-related genes were examined. Results showed that fish subjected to higher stocking density presented lower final body weights (FBW), specific growth ratio (SGR), and gonad adipose tissue index (GAI) (P density lipoprotein cholesterol (HDL-C) decreased significantly with increasing stocking density, while no significant change was observed for low-density lipoprotein cholesterol (LDL-C). Furthermore, the cDNAs encoding lipoprotein lipase (LPL) and hepatic lipase (HL) were isolated in Amur sturgeon, respectively. The full-length LPL cDNA was composed of 1757 bp with an open reading frame of 501 amino acids, while the complete nucleotide sequences of HL covered 1747 bp encoding 499 amino acids. In the liver, the activities and mRNA levels of LPL were markedly lower in HSD group, which were consistent with the variation tendency of HL. Fish reared in HSD group also presented lower levels of activities and mRNA expression of LPL in the muscle and gonad. Moreover, the expressions of peroxisome proliferator-activated receptor α (PPARα) in both the liver and skeletal muscle were significantly upregulated in HSD group. Overall, the results indicated that high stocking density negatively affects growth performance and lipid deposition of Amur sturgeon to a certain extent. The downregulation of LPL and HL and the upregulation of PPARα may be responsible for the lower lipid distribution of Amur sturgeon in higher stocking density.

Transvascular low-density lipoprotein transport in patients with diabetes mellitus (type 2)

DEFF Research Database (Denmark)

Kornerup, Karen; Nordestgaard, Børge Grønne; Feldt-Rasmussen, Bo

2002-01-01

accumulation and, thus, atherosclerosis. METHODS AND RESULTS: We developed an in vivo method for measurement of transvascular transport of low density lipoprotein (LDL) and applied it in 16 patients with maturity-onset diabetes (type 2) and 29 healthy control subjects. Autologous 131I-labeled LDL...... plasma insulin levels in diabetic patients. CONCLUSIONS: Transvascular LDL transport may be increased in patients with type 2 diabetes. This suggests that lipoprotein flux into the arterial wall is increased in people with diabetes, possibly explaining the accelerated development of atherosclerosis....... in patients with diabetes and control subjects, respectively (P2.5%/h and 5.3+/-1.6%/h (P

Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase.

Science.gov (United States)

Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M; Brown, Robert J

2014-09-05

Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL. Copyright © 2014 Elsevier Inc. All rights reserved.

Moderate doses of alcoholic beverages with dinner and postprandial high density lipoprotein composition

NARCIS (Netherlands)

Hendriks, H.F.J.; Veenstra, J.; Tol, A. van; Groener, J.E.M.; Schaafsma, G.

1998-01-01

Moderate alcohol consumption is associated with a reduced risk of coronary heart disease. In this study, postprandial changes in plasma lipids, high-density lipoprotein (HDL) composition and cholesteryl ester transfer protein (CETP) and lecithin: cholesterol acyltransferase (LCAT) activity levels

Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease.

Science.gov (United States)

Varbo, Anette; Benn, Marianne; Smith, George Davey; Timpson, Nicholas J; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G

2015-02-13

Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se. To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein. Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively. The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss. © 2014 American Heart Association, Inc.

High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus

DEFF Research Database (Denmark)

Drew, Brian G; Duffy, Stephen J; Formosa, Melissa F

2009-01-01

BACKGROUND: Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP...

[Alterations in the protein content and dysfunction of high-density lipoproteins from hyperhomocysteinemic mice].

Science.gov (United States)

Julve, Josep; Errico, Teresa Laura; Chen, Xiangyu; Santos, David; Freixa, Júlia; Porcel, Inmaculada; Cubero, Esther; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

2013-01-01

The aim of this study was to evaluate the proteic changes in high-density lipoproteins (HDL) induced by methionine-induced hyperhomocysteinemia in mice and its relationship with two of their main antiatherogenic properties. The oral administration of methionine resulted in an elevation (~8 times) in the plasma concentration of homocysteine. Hyperhomocysteinemia was inversely correlated with the plasma concentration of HDL cholesterol and its main protein component of HDL, apolipoprotein (apo) A-I, respectively. The cholesterol efflux in vivo from macrophages to HDL was decreased in hyperhomocysteinemic mice compared with the control mice. However, the reverse cholesterol transport from macrophages to feces remained unchanged. On the other hand, the ability of HDL from hyperhomocysteinemic mice to prevent the oxidative modification of low-density lipoproteins (LDL) was found decreased and associated with a concomitant reduction in the plasma activity of paraoxonase-1 (PON1) and the plasma concentration of apoA-I, and with a relative reduction in the apoA-IV content (~1.5 times) in the hyperhomocysteinemic HDL, respectively. The decrease in the ability of HDL from hyperhomocysteinemic mice to prevent LDL from oxidation was associated with a decrease in the apoA-I, PON1 and apoA-IV. Copyright © 2013 Elsevier España, S.L. and SEA. All rights reserved.

One precursor, three apolipoproteins: the relationship between two crustacean lipoproteins, the large discoidal lipoprotein and the high density lipoprotein/β-glucan binding protein.

Science.gov (United States)

Stieb, Stefanie; Roth, Ziv; Dal Magro, Christina; Fischer, Sabine; Butz, Eric; Sagi, Amir; Khalaila, Isam; Lieb, Bernhard; Schenk, Sven; Hoeger, Ulrich

2014-12-01

The novel discoidal lipoprotein (dLp) recently detected in the crayfish, differs from other crustacean lipoproteins in its large size, apoprotein composition and high lipid binding capacity, We identified the dLp sequence by transcriptome analyses of the hepatopancreas and mass spectrometry. Further de novo assembly of the NGS data followed by BLAST searches using the sequence of the high density lipoprotein/1-glucan binding protein (HDL-BGBP) of Astacus leptodactylus as query revealed a putative precursor molecule with an open reading frame of 14.7 kb and a deduced primary structure of 4889 amino acids. The presence of an N-terminal lipid bind- ing domain and a DUF 1943 domain suggests the relationship with the large lipid transfer proteins. Two-putative dibasic furin cleavage sites were identified bordering the sequence of the HDL-BGBP. When subjected to mass spectroscopic analyses, tryptic peptides of the large apoprotein of dLp matched the N-terminal part of the precursor, while the peptides obtained for its small apoprotein matched the C-terminal part. Repeating the analysis in the prawn Macrobrachium rosenbergii revealed a similar protein with identical domain architecture suggesting that our findings do not represent an isolated instance. Our results indicate that the above three apolipoproteins (i.e HDL-BGBP and both the large and the small subunit of dLp) are translated as a large precursor. Cleavage at the furin type sites releases two subunits forming a heterodimeric dLP particle, while the remaining part forms an HDL-BGBP whose relationship with other lipoproteins as well as specific functions are yet to be elucidated.

Comparison of a direct enzymatic assay and polyacrylamide tube gel electrophoresis for measurement of small, dense low-density lipoprotein cholesterol.

Science.gov (United States)

Vanavanan, Somlak; Srisawasdi, Pornpen; Rochanawutanon, Mana; Kerdmongkol, Jirapa; Kroll, Martin H

2015-01-01

Small, dense low-density lipoprotein cholesterol (sdLDL-C) has been linked to the progression of cardiovascular disease. We compared two methods for determination of sdLDL-C, a direct enzymatic (ENZ) method and a polyacrylamide tube gel electrophoresis (PGE) assay, and investigated the associations of both sdLDL-C measurements with metabolic syndrome. We analyzed 242 patient sera for sdLDL and atherosclerosis-related markers. The PGE method separates the intermediate-density lipoprotein particles into three midbands (MID-A to MID-C) and the LDL particles into seven subfractions (LDL1 to LDL7); the sdLDL-PGE result is calculated as the sum of cholesterol concentrations from LDL3 to LDL7. The regression equation for sdLDL-C was [ENZmmol/L]=0.779[PGE]+0.67, r=0.713. ENZ showed higher sdLDL-C concentrations than PGE (0.86±0.33 vs. 0.24±0.32 mmol/L); however, the difference was not associated with sdLDL-C concentration (p=0.290). sdLDL-C, as measured with the enzymatic assay, exhibited significant positive correlations with very-low-density lipoprotein, MID-C, MID-B, and LDL2 (all p0.600). The ENZ and PGE methods yielded similar patterns of correlation between sdLDL-C, and atherosclerosis-related markers. Using logistic regression, sdLDL-ENZ and apolipoprotein B were identified as significant predictors of metabolic syndrome (p<0.03). The ENZ assay for sdLDL-C correlated well with the PGE method. The ENZ method measures a broader range of atherogenic lipoprotein particles than PGE and has the potential to identify subjects with vascular risk, thus contributing in directing specific interventions for cardiovascular prevention.

Low density lipoprotein sensor based on surface plasmon resonance

International Nuclear Information System (INIS)

Matharu, Zimple; Sumana, G.; Pandey, M.K.; Gupta, Vinay; Malhotra, B.D.

2009-01-01

Biotinylated heparin has been immobilized onto self-assembled monolayer of 4-aminothiophenol using avidin-biotin specific binding. The modified electrodes have been characterized using surface plasmon resonance technique (SPR), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM) and contact angle (CA) measurements. The interaction of immobilized biotinylated heparin with low density lipoprotein (LDL) has been studied using surface plasmon resonance technique. The biotinylated heparin modified electrode can be used to detect LDL in the range of 20 to 100 mg/dl with the sensitivity of 513.3 m o /μM.

Low density lipoprotein sensor based on surface plasmon resonance

Energy Technology Data Exchange (ETDEWEB)

Matharu, Zimple [Department of Science and Technology Centre on Biomolecular Electronics, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Department of Physics and Astrophysics, University of Delhi, New Delhi-110007 (India); Sumana, G.; Pandey, M.K. [Department of Science and Technology Centre on Biomolecular Electronics, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Gupta, Vinay [Department of Physics and Astrophysics, University of Delhi, New Delhi-110007 (India); Malhotra, B.D., E-mail: bansi.malhotra@gmail.co [Department of Science and Technology Centre on Biomolecular Electronics, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India)

2009-11-30

Biotinylated heparin has been immobilized onto self-assembled monolayer of 4-aminothiophenol using avidin-biotin specific binding. The modified electrodes have been characterized using surface plasmon resonance technique (SPR), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM) and contact angle (CA) measurements. The interaction of immobilized biotinylated heparin with low density lipoprotein (LDL) has been studied using surface plasmon resonance technique. The biotinylated heparin modified electrode can be used to detect LDL in the range of 20 to 100 mg/dl with the sensitivity of 513.3 m{sup o}/{mu}M.

High-Density and Very-Low-Density Lipoprotein Have Opposing Roles in Regulating Tumor-Initiating Cells and Sensitivity to Radiation in Inflammatory Breast Cancer

Energy Technology Data Exchange (ETDEWEB)

Wolfe, Adam R. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Atkinson, Rachel L. [Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Reddy, Jay P. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Debeb, Bisrat G.; Larson, Richard; Li, Li [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Masuda, Hiroko; Brewer, Takae [Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Atkinson, Bradley J. [Department of Clinical Pharmacy Services, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Brewster, Abeena [Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Ueno, Naoto T. [Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Woodward, Wendy A., E-mail: wwoodward@mdanderson.org [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2015-04-01

Purpose: We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. Methods and Materials: Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. Results: VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015). Conclusions: This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients

High-Density and Very-Low-Density Lipoprotein Have Opposing Roles in Regulating Tumor-Initiating Cells and Sensitivity to Radiation in Inflammatory Breast Cancer

International Nuclear Information System (INIS)

Wolfe, Adam R.; Atkinson, Rachel L.; Reddy, Jay P.; Debeb, Bisrat G.; Larson, Richard; Li, Li; Masuda, Hiroko; Brewer, Takae; Atkinson, Bradley J.; Brewster, Abeena; Ueno, Naoto T.; Woodward, Wendy A.

2015-01-01

Purpose: We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. Methods and Materials: Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. Results: VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015). Conclusions: This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients

Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women

NARCIS (Netherlands)

Balder, Jan-Willem; Rimbert, Antoine; Zhang, Xiang; Viel, Martijn; Kanninga, Roan; van Dijk, Freerk; Lansberg, Peter; Sinke, Richard; Kuivenhoven, Jan Albert

2018-01-01

BACKGROUND: Atherosclerosis starts in childhood but low-density lipoprotein cholesterol (LDL-C), a causal risk factor, is mostly studied and dealt with when clinical events have occurred. Women are usually affected later in life than men and are underdiagnosed, undertreated, and understudied in

Oxidized low-density lipoproteins may induce expression of monocyte chemotactic protein-3 in atherosclerotic plaques

International Nuclear Information System (INIS)

Jang, Moon Kyoo; Kim, Ji Young; Jeoung, Nam Ho; Kang, Mi Ae; Choi, Myung-Sook; Oh, Goo Taeg; Nam, Kyung Tak; Lee, Won-Ha; Park, Yong Bok

2004-01-01

Genes induced or suppressed by oxidized low-density lipoproteins (oxLDL) in human monocytic THP-1 cells were searched using the differential display reverse transcriptase polymerase chain reaction. One of the differentially expressed (up-regulated) cDNA fragments was found to contain sequences corresponding to monocyte chemotactic protein-3 (MCP-3). The stimulatory effect of the oxLDL on the expression of MCP-3 mRNA was both time- and dose-dependent. Treatment with GF109203X and genistein, inhibitors of protein kinase C and tyrosine kinase, respectively, had no effect on the induction of MCP-3 mRNA by oxLDL, while treatment with cycloheximide inhibited the induction. The induction was reproduced by the lipid components in oxLDL such as 9-HODE and 13-HODE, which are known to activate the peroxisome proliferator-activated receptor γ (PPARγ). Introduction of an endogenous PPARγ ligand, 15d-PGJ2, in the culture of THP-1 cells resulted in the induction of MCP-3 gene expression. Furthermore, analyses of human atherosclerotic plaques revealed that the expressional pattern of MCP-3 in the regions of neointimal and necrotic core overlapped with that of PPARγ. These results suggest that oxLDL delivers its signal for MCP-3 expression via PPARγ, which may be further related to the atherogenesis

Kinetics of incorporation/redistribution of photosensitizer hypericin to/from high-density lipoproteins.

Science.gov (United States)

Joniova, Jaroslava; Buriankova, Luboslava; Buzova, Diana; Miskovsky, Pavol; Jancura, Daniel

2014-11-20

By means of fluorescence spectroscopy we have studied the kinetics of interaction of a photosensitizer hypericin (Hyp) with high-density lipoproteins (HDL). Hyp is incorporated into HDL molecules as monomer till ratio Hyp/HDL ∼8:1 and above this ratio forms non-fluorescent aggregates. This number is different from that found in the case of Hyp incorporation into low-density lipoprotein (LDL) molecules (8:1 vs 30:1). The difference is mainly attributed to the smaller size of HDL in comparison with LDL molecule. Biphasic kinetics of Hyp association with HDL was observed. The rapid phase of incorporation is completed within seconds, while the slow one lasts several minutes. The kinetics of the association of Hyp molecules with free HDL, Hyp/HDL=10:1 complex and the redistribution of Hyp from Hyp/HDL=70:1 complex to free HDL molecules reveal a qualitative similar characteristics of these processes with those observed for the interaction of Hyp with LDL. However, the incorporation of Hyp into HDL in the "slow" phase is more rapid than to LDL and extend of Hyp penetration into lipoproteins in the fast phase is also much higher in the case of HDL. The lower concentration of cholesterol molecules in outer shell of HDL particles is probably the determining factor for the more rapid kinetics of Hyp incorporation to and redistribution from these molecules when comparing with LDL particles. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

Science.gov (United States)

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.

Directory of Open Access Journals (Sweden)

Martin F Dietrich

2010-04-01

Full Text Available The low-density lipoprotein (LDL receptor gene family is a highly conserved group of membrane receptors with diverse functions in developmental processes, lipoprotein trafficking, and cell signaling. The low-density lipoprotein (LDL receptor-related protein 1b (LRP1B was reported to be deleted in several types of human malignancies, including non-small cell lung cancer. Our group has previously reported that a distal extracellular truncation of murine Lrp1b that is predicted to secrete the entire intact extracellular domain (ECD is fully viable with no apparent phenotype.Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normal trafficking through the secretary pathway. Both mutations result in early embryonic lethality, but, as expected from the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b-deficient blastocysts can be propagated normally in culture. This is similar to findings for another LDL receptor family member, Lrp4. We provide in vitro evidence that Lrp4 undergoes regulated intramembraneous processing through metalloproteases and gamma-secretase cleavage. We further demonstrate negative regulation of the Wnt signaling pathway by the soluble extracellular domain.Our results underline a crucial role for Lrp1b in development. The expression in mice of truncated alleles of Lrp1b and Lrp4 with deletions of the transmembrane and intracellular domains leads to release of the extracellular domain into the extracellular space, which is sufficient to confer viability. In contrast, null mutations are embryonically (Lrp1b or perinatally (Lrp4 lethal. These findings suggest that the extracellular domains of both proteins may function as a scavenger for signaling ligands or signal modulators in the extracellular space, thereby

Low density lipoprotein : structure, dynamics, and interactions of apoB-100 with lipids

NARCIS (Netherlands)

Murtola, T.; Vuorela, T.A.; Hyvönen, M.T.; Marrink, S.J.; Karttunen, M.E.J.; Vattulainen, I.

2011-01-01

Low-density lipoprotein (LDL) transports cholesterol in the bloodstream and plays an important role in the development of cardiovascular diseases, in particular atherosclerosis. Despite its importance to health, the structure of LDL is not known in detail. This is worrying since the lack of LDL's

Assessing the functional properties of high-density lipoproteins : an emerging concept in cardiovascular research

NARCIS (Netherlands)

Triolo, Michela; Annema, Wijtske; Dullaart, Robin P. F.; Tietge, Uwe J. F.

Although plasma concentrations of high-density lipoprotein (HDL) cholesterol correlate inversely with the incidence of atherosclerotic cardiovascular disease, results from recent epidemiological, genetic and pharmacological intervention studies resulted in a shift of concept. Rather than HDL

Association of peroxisome proliferator-activated receptor single-nucleotide polymorphisms and gene-gene interactions with the lipoprotein(a)

Institute of Scientific and Technical Information of China (English)

解惠坚

2014-01-01

Objective To examine the associations of 10 singlenucleotide polymorphisms(SNPs)in peroxisome proliferator-activated receptor(PPARs)gene with lipoprotein(a)level,and to investigate if there is gene-gene interaction among the SNPs on lipoprotein(a)level.Methods Totally 644 subjects(234 men and 410 women)were enrolled from Prevention of Multiple Metabolic Disorders and Metabolic Syndrome Study Cohort,which was an urban community survey study conducted in Jiangsu province.Ten SNPs in PPARα(rs135539,rs4253778,

Expressions of the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase genes are stimulated by recombinant platelet-derived growth factor isomers

International Nuclear Information System (INIS)

Roth, M.; Emmons, L.R.; Perruchoud, A.; Block, L.H.

1991-01-01

The plausible role that platelet-derived growth factor (PDGF) has in the localized pathophysiological changes that occur in the arterial wall during development of atherosclerotic lesions led the authors to investigate the influence of recombinant (r)PDGF isomers -AA, -AB, and -BB on the expression of low density lipoprotein receptor (LDL-R) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG0CoA) reductase [(S)-mevalonate:NAD + oxidoreductase (CoA-acylating), EC 1.1.1.88] genes. In addition, they clarified the role of protein kinase C (PKC) in expression of the two genes in human skin fibroblasts and vascular smooth muscle cells. The various rPDGF isoforms are distinct in their ability to activate transcription of both genes: (i) both rPDGF-AA and -BB stimulate transcription of the LDL-R gene; in contrast, rPDGF-BB but not -AA, activates transcription of the HMG-CoA reductase gene; (ii) all recombinant isoforms of PDGF activate transcription of the c-fos gene; (iii) while rPDGF-dependent transcription of the lDL-R gene occurs independently of PKC, transcription of the HMG-CoA reductase gene appears to involve the action of that enzyme

Uptake of [3H]vitamin D3 from low and high density lipoproteins by cultured human fibroblasts

International Nuclear Information System (INIS)

Shireman, R.B.; Williams, D.; Remsen, J.F.

1986-01-01

The plasma distribution and cellular uptake of [ 3 H]vitamin D 3 was studied in vitro using cultured human fibroblasts. Incubation of [ 3 H]vitamin D 3 (cholecalciferol) with plasma followed by sequential ultracentrifugal fractionation of the lipoproteins indicated that 2-4% of the radioactivity associated with the very low density lipoprotein (VLDL), 12% with low density lipoprotein (LDL), and approximately 60% with the high density lipoprotein (HDL). The remaining radioactivity, 25%, was associated with the sedimented plasma fractions. By comparison, an average of 86% of the radioactivity from [ 3 H] 1,25-dihydroxycholecalciferol associated with the sedimented plasma fractions. The uptake of [ 3 H]vitamin D 3 from plasma, LDL, or HDL was studied in cultured human cells; uptake by normal fibroblasts was greatest from LDL and least from plasma. The cellular association of vitamin D 3 was time, concentration, and temperature dependent. At a concentration of 50 μg LDL/ml of medium, the uptake of [ 3 H]vitamin D 3 from LDL at 37 0 C was rapid and reached a maximum at approximately 4 hr; it was slower from HDL but continued to increase slowly up to 24 hr. The significance of these in vitro findings is uncertain since much of the vitamin D 3 absorbed from the intestine reportedly associates with chylomicrons and is rapidly taken up by the liver

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats.

Science.gov (United States)

Rojas, Jennifer M; Stafford, John M; Saadat, Sanaz; Printz, Richard L; Beck-Sickinger, Annette G; Niswender, Kevin D

2012-12-15

Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed Long-Evans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed Long-Evans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.

High density lipoprotein cholesterol (HDL) metabolism and its role in ischemic heart disease

International Nuclear Information System (INIS)

Pirzado, Z.A.; Sngi, S.A.; Malik, R.

1999-01-01

Case control and prospective epidemiological studies have found a striking, consistently negative association between High Density Lipoprotein(HDL) levels and coronary vascular events. As a results, the genetic and environmental determinants of HDL levels are being studied intensively. These investigations and their potential clinical applications require a fundamental understanding of the structure, function and metabolism of HDL and its components. Of the special interest are the means by which it exerts its apparently protective effect. In this report we characterize the structure of HLD: and describe its compounds, particularly the protein component. We discuss HDL metabolism in light of the relationship of HDL to other lipoprotein classes and relate what little is known of the functions of HDL. We also review the biochemical mechanism by which HDL may protect against cardiovascular disease and discuss further biochemical research that will be necessary for a better understanding of HDL. Interest in HDL has been greatly intensified in recent years, stimulated largely by the finding that HDL is inversely related in HDL has been greatly intensified in recent years, stimulated largely by the finding that HDL is inversely related to coronary artery disease. Case-control and prospective observations of the striking, consistent and independent negative association between HDL levels and coronary vascular events have in turn generated new interest in the structure, composition and metabolism of these fascinating lipoproteins. Several studies carried out in Pakistan also reveal the inverse relation of HDL to IHD/sup 1,2/. This article contains a tremendous amount of information on HDL and its relationship to genetic and environmental factors which should be useful to investigations and clinicians in their evaluation and use of HDL cholesterol measurements to assess hearth disease risk. A knowledge of the structure, function and metabolism of HDL and its components is

Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection.

Directory of Open Access Journals (Sweden)

Marie Samanovic

2009-01-01

Full Text Available Innate immunity is the first line of defense against invading microorganisms. Trypanosome Lytic Factor (TLF is a minor sub-fraction of human high-density lipoprotein that provides innate immunity by completely protecting humans from infection by most species of African trypanosomes, which belong to the Kinetoplastida order. Herein, we demonstrate the broader protective effects of human TLF, which inhibits intracellular infection by Leishmania, a kinetoplastid that replicates in phagolysosomes of macrophages. We show that TLF accumulates within the parasitophorous vacuole of macrophages in vitro and reduces the number of Leishmania metacyclic promastigotes, but not amastigotes. We do not detect any activation of the macrophages by TLF in the presence or absence of Leishmania, and therefore propose that TLF directly damages the parasite in the acidic parasitophorous vacuole. To investigate the physiological relevance of this observation, we have reconstituted lytic activity in vivo by generating mice that express the two main protein components of TLFs: human apolipoprotein L-I and haptoglobin-related protein. Both proteins are expressed in mice at levels equivalent to those found in humans and circulate within high-density lipoproteins. We find that TLF mice can ameliorate an infection with Leishmania by significantly reducing the pathogen burden. In contrast, TLF mice were not protected against infection by the kinetoplastid Trypanosoma cruzi, which infects many cell types and transiently passes through a phagolysosome. We conclude that TLF not only determines species specificity for African trypanosomes, but can also ameliorate an infection with Leishmania, while having no effect on T. cruzi. We propose that TLFs are a component of the innate immune system that can limit infections by their ability to selectively damage pathogens in phagolysosomes within the reticuloendothelial system.

Phytosterols, Phytostanols, and Lipoprotein Metabolism

Directory of Open Access Journals (Sweden)

Helena Gylling

2015-09-01

Full Text Available The efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and low density lipoprotein (LDL cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia and, even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%–10%. They do not affect the concentrations of high density lipoprotein cholesterol, lipoprotein (a or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly increased baseline concentrations. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Cholesterol absorption and synthesis have been carefully evaluated during phytosterol and phytostanol supplementation. However, only a few lipoprotein kinetic studies have been performed, and they revealed that LDL apoprotein B-100 transport rate was reduced. LDL particle size was unchanged, but small dense LDL cholesterol concentration was reduced. In subjects with metabolic syndrome and moderate hypertriglyceridemia, phytostanols reduced not only non- high density lipoprotein (HDL cholesterol concentration but also serum triglycerides by 27%, and reduced the large and medium size very low density lipoprotein particle concentrations. In the few postprandial studies, the postprandial lipoproteins were reduced, but detailed studies with apoprotein B-48 are lacking. In conclusion, more kinetic studies are required to obtain a more complete understanding of the fasting and postprandial lipoprotein metabolism caused by phytosterols and phytostanols. It seems obvious, however, that the most atherogenic lipoprotein

Phytosterols, Phytostanols, and Lipoprotein Metabolism.

Science.gov (United States)

Gylling, Helena; Simonen, Piia

2015-09-17

The efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and low density lipoprotein (LDL) cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia and, even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%-10%. They do not affect the concentrations of high density lipoprotein cholesterol, lipoprotein (a) or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly increased baseline concentrations. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Cholesterol absorption and synthesis have been carefully evaluated during phytosterol and phytostanol supplementation. However, only a few lipoprotein kinetic studies have been performed, and they revealed that LDL apoprotein B-100 transport rate was reduced. LDL particle size was unchanged, but small dense LDL cholesterol concentration was reduced. In subjects with metabolic syndrome and moderate hypertriglyceridemia, phytostanols reduced not only non- high density lipoprotein (HDL) cholesterol concentration but also serum triglycerides by 27%, and reduced the large and medium size very low density lipoprotein particle concentrations. In the few postprandial studies, the postprandial lipoproteins were reduced, but detailed studies with apoprotein B-48 are lacking. In conclusion, more kinetic studies are required to obtain a more complete understanding of the fasting and postprandial lipoprotein metabolism caused by phytosterols and phytostanols. It seems obvious, however, that the most atherogenic lipoprotein particles will be

Quantitative studies of transfer in vivo of low density, Sf 12-60, and Sf 60-400 lipoproteins between plasma and arterial intima in humans

International Nuclear Information System (INIS)

Shaikh, M.; Wootton, R.; Nordestgaard, B.G.; Baskerville, P.; Lumley, J.S.; La Ville, A.E.; Quiney, J.; Lewis, B.

1991-01-01

To assess the potential of various plasma lipoprotein classes to contribute to the lipid content of the arterial intima, influx and efflux of these plasma lipoprotein fractions into and from the intima of human carotid arteries were measured in vivo. While low density lipoprotein (LDL) is known to transfer from plasma into the arterial wall, there is less information on the atherogenic potential of lipoproteins of intermediate density (Sf 12-60) or of very low density (Sf 60-400). Aliquots of the same lipoprotein (LDL, Sf 12-60 lipoprotein particles, or Sf 60-400 lipoprotein particles) iodinated with iodine-125 and iodine-131 were injected intravenously 18-29 hours and 3-6 hours, respectively, before elective surgical removal of atheromatous arterial tissue, and the intimal clearance of lipoproteins, lipoprotein influx, and fractional loss of newly entered lipoproteins were calculated. Intimal clearance of Sf 60-400 particles was not detectable (less than 0.3 microliter x hr-1 x cm-2), whereas the average value for both LDL and Sf 12-60 lipoprotein particles was 0.9 microliter x hr-1 x cm-2. Since the fractional loss of newly entered LDL and Sf 12-60 lipoprotein particles was also similar, the results suggest similar modes of entry and exit for these two particles. However, due to lower plasma concentrations of Sf 12-60 lipoproteins as compared with LDL, the mass influx of cholesterol in the Sf 12-60 particles was on the order of one 10th of that in LDL, and that of apolipoprotein B was about one 20th

Apolipoprotein A-V Deficiency Results in MarkedHypertriglyceridemia Attributable to Decreased Lipolysis ofTriglyceride-Rich Lipoproteins and Removal of Their Remnants

Energy Technology Data Exchange (ETDEWEB)

Grosskopf, Itamar; Baroukh, Nadine; Lee, Sung-Joon; Kamari,Yehuda; Harats, Dror; Rubin, Edward M.; Pennacchio, Len A.; Cooper, AllenD.

2005-09-01

Objective--ApoAV, a newly discovered apoprotein, affectsplasma triglyceride level. To determine how this occurs, we studiedtriglyceride-rich lipoprotein (TRL) metabolism in mice deficient inapoAV. Methods and Results No significant difference in triglycerideproduction rate was found between apoa5_/_ mice and controls. Thepresence or absence of apoAV affected TRL catabolism. After the injectionof 14C-palmitate and 3H-cholesterol labeled chylomicrons and 125I-labeledchylomicron remnants, the disappearance of 14C, 3H, and 125I wassignificantly slower in apoa5_/_ mice relative to controls. This wasbecause of diminished lipolysis of TRL and the reduced rate of uptake oftheir remnants in apoa5_/_ mice. Observed elevated cholesterol level wascaused by increased high-density lipoprotein (HDL) cholesterol inapoa5_/_ mice. VLDL from apoa5_/_ mice were poor substrate forlipoprotein lipase, and did not bind to the low-density lipoprotein (LDL)receptor as well as normal very-low-density lipoprotein (VLDL). LDLreceptor levels were slightly elevated in apoa5_/_ mice consistent withlower remnant uptake rates. These alterations may be the result of thelower apoE-to-apoC ratio found in VLDL isolated from apoa5_/_mice.Conclusions These results support the hypothesis that the absence ofapoAV slows lipolysis of TRL and the removal of their remnants byregulating their apoproteins content after secretion.

Extract of mangosteen increases high density lipoprotein levels in rats fed high lipid

Directory of Open Access Journals (Sweden)

Dwi Laksono Adiputro

2013-04-01

Full Text Available Background In cardiovascular medicine, Garcinia mangostana has been used as an antioxidant to inhibit oxidation of low density lipoproteins and as an antiobesity agent. The effect of Garcinia mangostana on hyperlipidemia is unknown. The aim of this study was to evaluate the effect of an ethanolic extract of Garcinia mangostana pericarp on lipid profile in rats fed a high lipid diet. Methods A total of 40 rats were divided into five groups control, high lipid diet, and high lipid diet + ethanolic extract of Garcinia mangostana pericarp at dosages of 200, 400, and 800 mg/kg body weight. The control group received a standard diet for 60 days. The high lipid diet group received standard diet plus egg yolk, goat fat, cholic acid, and pig fat for 60 days with or without ethanolic extract of Garcinia mangostana pericarp by the oral route. After 60 days, rats were anesthesized with ether for collection of blood by cardiac puncture. Analysis of blood lipid profile comprised colorimetric determination of cholesterol, triglyceride, low density lipoprotein (LDL, and high density lipoprotein (HDL. Results From the results of one-way ANOVA it was concluded that there were significant between-group differences in cholesterol, trygliceride, LDL, and HDL levels (p=0.000. Ethanolic extract of Garcinia mangostana pericarp significantly decreased cholesterol, trygliceride, and LDL levels, starting at 400 mg/kg body weight (p=0.000. Ethanolic extract of Garcinia mangostana pericarp significantly increased HDL level starting at 200 mg/kg body weight (p=0.000. Conclusion Ethanolic extract of Garcinia mangostana pericarp has a beneficial effect on lipid profile in rats on a high lipid diet.

Extract of mangosteen increases high density lipoprotein levels in rats fed high lipid

Directory of Open Access Journals (Sweden)

Dwi Laksono Adiputro

2015-12-01

Full Text Available BACKGROUND In cardiovascular medicine, Garcinia mangostana has been used as an antioxidant to inhibit oxidation of low density lipoproteins and as an antiobesity agent. The effect of Garcinia mangostana on hyperlipidemia is unknown. The aim of this study was to evaluate the effect of an ethanolic extract of Garcinia mangostana pericarp on lipid profile in rats fed a high lipid diet. METHODS A total of 40 rats were divided into five groups control, high lipid diet, and high lipid diet + ethanolic extract of Garcinia mangostana pericarp at dosages of 200, 400, and 800 mg/kg body weight. The control group received a standard diet for 60 days. The high lipid diet group received standard diet plus egg yolk, goat fat, cholic acid, and pig fat for 60 days with or without ethanolic extract of Garcinia mangostana pericarp by the oral route. After 60 days, rats were anesthesized with ether for collection of blood by cardiac puncture. Analysis of blood lipid profile comprised colorimetric determination of cholesterol, triglyceride, low density lipoprotein (LDL, and high density lipoprotein (HDL. RESULTS From the results of one-way ANOVA it was concluded that there were significant between-group differences in cholesterol, trygliceride, LDL, and HDL levels (p=0.000. Ethanolic extract of Garcinia mangostana pericarp significantly decreased cholesterol, trygliceride, and LDL levels, starting at 400 mg/kg body weight (p=0.000. Ethanolic extract of Garcinia mangostana pericarp significantly increased HDL level starting at 200 mg/kg body weight (p=0.000. CONCLUSION Ethanolic extract of Garcinia mangostana pericarp has a beneficial effect on lipid profile in rats on a high lipid diet.

Preferential enrichment of large-sized very low density lipoprotein populations with transferred cholesteryl esters

International Nuclear Information System (INIS)

Eisenberg, S.

1985-01-01

The effect of lipid transfer proteins on the exchange and transfer of cholesteryl esters from rat plasma HDL2 to human very low (VLDL) and low density (LDL) lipoprotein populations was studied. The use of a combination of radiochemical and chemical methods allowed separate assessment of [ 3 H]cholesteryl ester exchange and of cholesteryl ester transfer. VLDL-I was the preferred acceptor for transferred cholesteryl esters, followed by VLDL-II and VLDL-III. LDL did not acquire cholesteryl esters. The contribution of exchange of [ 3 H]cholesteryl esters to total transfer was highest for LDL and decreased in reverse order along the VLDL density range. Inactivation of lecithin: cholesterol acyltransferase (LCAT) and heating the HDL2 for 60 min at 56 degrees C accelerated transfer and exchange of [ 3 H]cholesteryl esters. Addition of lipid transfer proteins increased cholesterol esterification in all systems. The data demonstrate that large-sized, triglyceride-rich VLDL particles are preferred acceptors for transferred cholesteryl esters. It is suggested that enrichment of very low density lipoproteins with cholesteryl esters reflects the triglyceride content of the particles

Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

NARCIS (Netherlands)

Kersten, A.H.

2008-01-01

Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that

Effects of insulin-like growth factor-1 on the assembly and secretion of very low-density lipoproteins in cow hepatocytes in vitro.

Science.gov (United States)

Li, Xinwei; Guan, Yuan; Li, Ying; Wu, Dianjun; Liu, Lei; Deng, Qinghua; Li, Xiaobing; Wang, Zhe; Liu, Guowen

2016-01-15

Fatty liver is a major metabolic disorder of dairy cows. One important reason is that hepatic very low-density lipoproteins (VLDL) assembly was significant decreased in dairy cows with fatty liver. In addition, the impairment of insulin-like growth factor (IGF)-1 synthesis was involved in the development of fatty liver. Therefore, the objective of this study was to investigate the effects of IGF-1 on the VLDL assembly in cow hepatocytes. In this study, cow hepatocytes were cultured and then transfected with Ad-GFP-IGF-1 (inhibited the IGF-1 expression) and Ad-GFP (negative control), and treated with different concentrations of IGF-1, respectively. The results showed that IGF-1 increased the mRNA abundance of apolipoprotein B100 (ApoB100), apolipoprotein E (ApoE), microsomal triglyceride transfer protein (MTTP), and low-density lipoprotein receptor (LDLR) and then increased the VLDL assembly in cow hepatocytes. Nevertheless, impairment of IGF-1 expression by Ad-GFP-IGF-1 could inhibit above genes expression and VLDL assembly in hepatocytes. Taken together, these results indicate that IGF-1 increases the VLDL assembly and impairment of IGF-1 expression decreases the VLDL assembly in cow hepatocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

Alterations of serum cholesterol and serum lipoprotein in breast cancer of women

OpenAIRE

Hasija, Kiran; Bagga, Hardeep K.

2005-01-01

Fasting blood sample of 50 normal subjects (control) and 100 patients of breast cancer were investigated for serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, very low density lipoprotein, high density lipoprotein cholesterol:low density lipoprotein cholesterol ratio and total cholesterol:high density lipoprotein cholesterol ratio during breast cancer of women. Five cancer stages, types, age groups, parity and menopausal status were undertaken...

Stimulation of cholesteryl ester synthesis in mouse peritoneal macrophages by cholesterol-rich very low density lipoproteins from the Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia

International Nuclear Information System (INIS)

Kita, T.; Yokode, M.; Watanabe, Y.; Narumiya, S.; Kawai, C.

1986-01-01

Cholesterol-rich very low density lipoproteins (VLDL) from the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbit induced marked cholesteryl ester accumulation in mouse peritoneal macrophages. This WHHL rabbit, an animal model of human familial hypercholesterolemia, has severe hypercholesterolemia, cutaneous xanthomas, and fulminant atherosclerosis due to the deficiency of the low density lipoprotein (LDL) receptor. When incubated with mouse peritoneal macrophages, the VLDL from WHHL rabbit (WHHL-VLDL) stimulated cholesteryl [ 14 C]oleate synthesis 124-fold more than did VLDL from the normal Japanese White rabbit (control-VLDL). The enhancement in cholesteryl ester synthesis and accumulation of WHHL-VLDL was due to the presence of a high affinity binding receptor site on the macrophage cell surface that mediated the uptake and lysosomal degradation of WHHL-VLDL. Competition studies showed that the uptake and degradation of 125 I-WHHL-VLDL was inhibited by unlabeled excess WHHL-VLDL and beta-migrating VLDL (beta-VLDL), but not LDL. Furthermore, the degradation of WHHL-VLDL was not blocked by either fucoidin, polyinosinic acid, or polyguanylic acid, potent inhibitors of the acetylated (acetyl)-LDL binding site, or by acetyl-LDL. These results suggest that macrophages possess a high affinity receptor that recognizes the cholesterol-rich VLDL present in the plasma of the WHHL rabbit and that the receptor which mediates ingestion of WHHL-VLDL seems to be the same as that for beta-VLDL and leads to cholesteryl ester deposition within macrophages. Thus, the uptake of the cholesterol-rich VLDL from the WHHL rabbit by macrophages in vivo may play a significant role in the pathogenesis of atherosclerosis in the WHHL rabbit

Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

DEFF Research Database (Denmark)

Feitosa, Mary F; Wojczynski, Mary K; Straka, Robert

2014-01-01

The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights...

Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein

NARCIS (Netherlands)

Schalkwijk, C.G.; Vermeer, M.A.; Stehouwer, C.D.A.; Koppele, J. te; Princen, H.M.G.; Hinsbergh, V.W.M. van

1998-01-01

In patients with diabetes, non-enzymatic glycation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis. α-Dicarbonyl compounds were identified as intermediates in the non-enzymatic glycation and increased levels were reported in patients with

Effects of aerobic exercise on lipids and lipoproteins.

Science.gov (United States)

Wang, Yating; Xu, Danyan

2017-07-05

Dyslipidemia is the risk of cardiovascular disease, and their relationship is clear. Lowering serum cholesterol can reduce the risk of coronary heart disease. At present, the main treatment is taking medicine, however, drug treatment has its limitations. Exercise not only has a positive effect on individuals with dyslipidemia, but can also help improve lipids profile. This review is intending to provide information on the effects of exercise training on both tranditional lipids, for example, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and new lipids and lipoproteins such as non-high-density lipoprotein cholesterol, and postprandial lipoprotein. The mechanisms of aerobic exercise on lipids and lipoproteins are also briefly described.

High-density lipoprotein cholesterol: How High

Directory of Open Access Journals (Sweden)

G Rajagopal

2012-01-01

Full Text Available The high-density lipoprotein cholesterol (HDL-C is considered anti-atherogenic good cholesterol. It is involved in reverse transport of lipids. Epidemiological studies have found inverse relationship of HDL-C and coronary heart disease (CHD risk. When grouped according to HDL-C, subjects having HDL-C more than 60 mg/dL had lesser risk of CHD than those having HDL-C of 40-60 mg/dL, who in turn had lesser risk than those who had HDL-C less than 40 mg/dL. No upper limit for beneficial effect of HDL-C on CHD risk has been identified. The goals of treating patients with low HDL-C have not been firmly established. Though many drugs are known to improve HDL-C concentration, statins are proven to improve CHD risk and mortality. Cholesteryl ester transfer protein (CETP is involved in metabolism of HDL-C and its inhibitors are actively being screened for clinical utility. However, final answer is still awaited on CETP-inhibitors.

Lipoprotein-associated phospholipase A2 distribution among lipoproteins differs in type 1 diabetes.

Science.gov (United States)

Jarvie, Jennifer L; Wang, Hong; Kinney, Gregory L; Snell-Bergeon, Janet; Hokanson, John E; Eckel, Robert H

2016-01-01

LpPLA2 mass and activity have been variably related to cardiovascular disease risk, and the distribution of LpPLA2 in patients with type 1 diabetes (T1D), wherein cardiovascular disease risk is high despite normal or higher levels of high-density lipoprotein (HDL) cholesterol, is unknown. To determine whether there are differences in the distribution of LpPLA2 mass and activity across lipoproteins and their association with coronary artery calcium (CAC) in patients with T1D. Men with T1D (n = 19) not on statins, with and without CAC progression, and men without diabetes matched for HDL cholesterol (n = 25) had lipoproteins separated by fast protein liquid chromatography. Both LpPLA2 mass and activity were found within low-density lipoprotein (LDL) and HDL pools with more LpPLA2 mass being associated with HDL (54% vs 44%; P-value lipoprotein subfractions was observed between all groups, and there was no relationship between LpPLA2 activity or mass and its distribution and CAC score progression in healthy or T1D men. LpPLA2 is found in both LDL and HDL and is distributed differently in men with T1D without any relationship to CAC score progression. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Contributions of a disulfide bond and a reduced cysteine side chain to the intrinsic activity of the high-density lipoprotein receptor SR-BI.

Science.gov (United States)

Yu, Miao; Lau, Thomas Y; Carr, Steven A; Krieger, Monty

2012-12-18

The high-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI), binds HDL and mediates selective cholesteryl ester uptake. SR-BI's structure and mechanism are poorly understood. We used mass spectrometry to assign the two disulfide bonds in SR-BI that connect cysteines within the conserved Cys(321)-Pro(322)-Cys(323) (CPC) motif and connect Cys(280) to Cys(334). We used site-specific mutagenesis to evaluate the contributions of the CPC motif and the side chain of extracellular Cys(384) to HDL binding and lipid uptake. The effects of CPC mutations on activity were context-dependent. Full wild-type (WT) activity required Pro(322) and Cys(323) only when Cys(321) was present. Reduced intrinsic activities were observed for CXC and CPX, but not XXC, XPX, or XXX mutants (X ≠ WT residue). Apparently, a free thiol side chain at position 321 that cannot form an intra-CPC disulfide bond with Cys(323) is deleterious, perhaps because of aberrant disulfide bond formation. Pro(322) may stabilize an otherwise strained CPC disulfide bond, thus supporting WT activity, but this disulfide bond is not absolutely required for normal activity. C(384)X (X = S, T, L, Y, G, or A) mutants exhibited altered activities that varied with the side chain's size: larger side chains phenocopied WT SR-BI treated with its thiosemicarbazone inhibitor BLT-1 (enhanced binding, weakened uptake); smaller side chains produced almost inverse effects (increased uptake:binding ratio). C(384)X mutants were BLT-1-resistant, supporting the proposal that Cys(384)'s thiol interacts with BLT-1. We discuss the implications of our findings on the functions of the extracellular loop cysteines in SR-BI and compare our results to those presented by other laboratories.

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid.

Science.gov (United States)

Mateuszuk, Lukasz; Jasztal, Agnieszka; Maslak, Edyta; Gasior-Glogowska, Marlena; Baranska, Malgorzata; Sitek, Barbara; Kostogrys, Renata; Zakrzewska, Agnieszka; Kij, Agnieszka; Walczak, Maria; Chlopicki, Stefan

2016-02-01

1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/LDLR(-/-) mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F1 α and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR(-/-) mice, an effect associated with an improvement in prostacyclin- and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA. Copyright © 2016 by The American Society for Pharmacology and Experimental

Serum Paraoxonase 1 Activity Is Associated with Fatty Acid Composition of High Density Lipoprotein

Directory of Open Access Journals (Sweden)

Maryam Boshtam

2013-01-01

Full Text Available Introduction. Cardioprotective effect of high density lipoprotein (HDL is, in part, dependent on its related enzyme, paraoxonase 1 (PON1. Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. Methods. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Results. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA. PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω6 fatty acids of HDL. Conclusion. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health.

Serum paraoxonase 1 activity is associated with fatty acid composition of high density lipoprotein.

Science.gov (United States)

Boshtam, Maryam; Razavi, Amirnader Emami; Pourfarzam, Morteza; Ani, Mohsen; Naderi, Gholam Ali; Basati, Gholam; Mansourian, Marjan; Dinani, Narges Jafari; Asgary, Seddigheh; Abdi, Soheila

2013-01-01

Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω 6 fatty acids of HDL. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health.

Biomimetic High Density Lipoprotein Nanoparticles For Nucleic Acid Delivery

Science.gov (United States)

McMahon, Kaylin M.; Mutharasan, R. Kannan; Tripathy, Sushant; Veliceasa, Dorina; Bobeica, Mariana; Shumaker, Dale K.; Luthi, Andrea J.; Helfand, Brian T.; Ardehali, Hossein; Mirkin, Chad A.; Volpert, Olga; Thaxton, C. Shad

2014-01-01

We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy which combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy (TEM), and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery. PMID:21319839

[A history and review of cholesterol ester transfer protein inhibitors and their contribution to the understanding of the physiology and pathophysiology of high density lipoprotein].

Science.gov (United States)

Corral, Pablo; Schreier, Laura

2014-01-01

There is irrefutable evidence that statins reduce the risk of cardiovascular events in a magnitude proportional to the intensity of the decrease in cholesterol transport by the low density lipoproteins. Despite this great advance there is still a residual risk of cardiovascular events. For this reason, an increase in the levels of high density lipoprotein is considered in order to boost the main action of this lipoprotein, which is reverse cholesterol transport. Distinct classes of evidence (epidemiological, genetic, and pathophysiological) show that the inhibition and/or modulation of cholesterol ester transfer protein increases plasma high density lipoprotein-cholesterol levels. The main reason for presenting this review is to look at the physiology of cholesterol ester transfer protein, its interrelationship with high density lipoproteins, and to give an update on the development of different cholesterol ester transfer protein inhibitor/modulator molecules. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men.

Science.gov (United States)

Riales, R; Albrink, M J

1981-12-01

Chromium deficiency may cause insulin resistance, hyperinsulinemia, impaired glucose tolerance, and hyperlipidemia, recovered by chromium supplementation. The effect of chromium supplementation on serum lipids and glucose tolerance was tested in a double-blind 12-wk study of 23 healthy adult men aged 31 to 60 yr. Either 200 micrograms trivalent chromium in 5 ml water (Cr) or 5 ml plain water (W) was ingested daily 5 days each week. Half the subjects volunteered for glucose tolerance tests with insulin levels. At 12 wk high-density lipoprotein cholesterol increased in the Cr group from 35 to 39 mg/dl (p less than 0.05) but did not change in the water group (34 mg/dl). The largest increase in high-density lipoprotein cholesterol and decreases in insulin and glucose were found in those subjects having normal glucose levels together with elevated insulin levels at base-line. The data are thus consistent with the hypothesis that Cr supplementation raises high-density lipoprotein cholesterol and improves insulin sensitivity in those with evidence of insulin resistance but normal glucose tolerance.

Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1

NARCIS (Netherlands)

Ljunggren, Stefan A.; Levels, Johannes H. M.; Hovingh, Kees; Holleboom, Adriaan G.; Vergeer, Menno; Argyri, Letta; Gkolfinopoulou, Christina; Chroni, Angeliki; Sierts, Jeroen A.; Kastelein, John J.; Kuivenhoven, Jan Albert; Lindahl, Mats; Karlsson, Helen

2015-01-01

The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1(P297S) mutation are characterized by increased HDL cholesterol

Genetics of Lipid and Lipoprotein Disorders and Traits.

Science.gov (United States)

Dron, Jacqueline S; Hegele, Robert A

2016-01-01

Plasma lipids, namely cholesterol and triglyceride, and lipoproteins, such as low-density lipoprotein (LDL) and high-density lipoprotein, serve numerous physiological roles. Perturbed levels of these traits underlie monogenic dyslipidemias, a diverse group of multisystem disorders. We are on the verge of having a relatively complete picture of the human dyslipidemias and their components. Recent advances in genetics of plasma lipids and lipoproteins include the following: (1) expanding the range of genes causing monogenic dyslipidemias, particularly elevated LDL cholesterol; (2) appreciating the role of polygenic effects in such traits as familial hypercholesterolemia and combined hyperlipidemia; (3) accumulating a list of common variants that determine plasma lipids and lipoproteins; (4) applying exome sequencing to identify collections of rare variants determining plasma lipids and lipoproteins that via Mendelian randomization have also implicated gene products such as NPC1L1 , APOC3 , LDLR , APOA5 , and ANGPTL4 as causal for atherosclerotic cardiovascular disease; and (5) using naturally occurring genetic variation to identify new drug targets, including inhibitors of apolipoprotein (apo) C-III, apo(a), ANGPTL3, and ANGPTL4. Here, we compile this disparate range of data linking human genetic variation to plasma lipids and lipoproteins, providing a "one stop shop" for the interested reader.

Accumulation of Oxidized Low-Density Lipoprotein in Psoriatic Skin and Changes of Plasma Lipid Levels in Psoriatic Patients

Directory of Open Access Journals (Sweden)

Nilgun Solak Tekin

2007-01-01

Full Text Available Background. Psoriasis is a chronic inflammatory skin disease characterized by an accelerated turnover of epidermal cells and an incomplete differentiation in epidermis with lesion. However, the exact etiology of psoriasis is unknown. Abnormalities in essential fatty acid metabolism, free radical generation, lipid peroxidation, and release of lymphokines have been proposed. Objective. Our purpose was to evaluate the plasma lipids and oxidized low-density lipoprotein accumulation in psoriatic skin lesion in order to ascertain the possible participation of oxidative stress and oxidative modification of lipids in pathogenesis of psoriasis. Methods. The study group included 84 patients with psoriasis, and 40 sex- and age-matched healthy volunteers. Blood lipid profile was determined. Psoriatic and nonlesional skin samples of psoriatic patients were evaluated for the presence of oxidized low-density lipoprotein by using an immune-fluorescent staining method. Results. The mean levels of lipids (total cholesterol, triglyceride, and LDL cholesterol in patients with psoriasis were found to be significantly higher than those of healthy subjects. Psoriatic skins were shown positive oxidized low-density lipoprotein staining. There was no staining in nonlesional skin samples of the same individuals. Conclusion. Lipid peroxidation mediated by free radicals is believed to be one of the important causes of cell membrane destruction and cell damage. This study shows for the first time the accumulation of oxidized low-density lipoprotein in psoriatic skin lesion. We believe that accumulation of ox-LDL in psoriatic skin may have an important role in the immune-inflammatory events that result in progressive skin damage.

Immunization with gingipain A hemagglutinin domain of Porphyromonas gingivalis induces IgM antibodies binding to malondialdehyde-acetaldehyde modified low-density lipoprotein.

Directory of Open Access Journals (Sweden)

Mikael Kyrklund

Full Text Available Treatment of periodontitis has beneficial effects on systemic inflammation markers that relate to progression of atherosclerosis. We aimed to investigate whether immunization with A hemagglutinin domain (Rgp44 of Porphyromonas gingivalis (Pg, a major etiologic agent of periodontitis, would lead to an antibody response cross-reacting with oxidized low-density lipoprotein (OxLDL and how it would affect the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLR-/- mice. The data revealed a prominent IgM but not IgG response to malondialdehyde-acetaldehyde modified LDL (MAA-LDL after Rgp44 and Pg immunizations, implying that Rgp44/Pg and MAA adducts may share cross-reactive epitopes that prompt IgM antibody production and consequently confer atheroprotection. A significant negative association was observed between atherosclerotic lesion and plasma IgA to Rgp44 in Rgp44 immunized mice, supporting further the anti-atherogenic effect of Rgp44 immunization. Plasma IgA levels to Rgp44 and to Pg in both Rgp44- and Pg-immunized mice were significantly higher than those in saline control, suggesting that IgA to Rgp44 could be a surrogate marker of immunization in Pg-immunized mice. Distinct antibody responses in plasma IgA levels to MAA-LDL, to Pg lipopolysaccharides (Pg-LPS, and to phosphocholine (PCho were observed after Rgp44 and Pg immunizations, indicating that different immunogenic components between Rpg44 and Pg may behave differently in regard of their roles in the development of atherosclerosis. Immunization with Rgp44 also displayed atheroprotective features in modulation of plaque size through association with plasma levels of IL-1α whereas whole Pg bacteria achieved through regulation of anti-inflammatory cytokine levels of IL-5 and IL-10. The present study may contribute to refining therapeutic approaches aiming to modulate immune responses and inflammatory/anti-inflammatory processes in atherosclerosis.

Gold nanocrystal labeling allows low-density lipoprotein imaging from the subcellular to macroscopic level

NARCIS (Netherlands)

Allijn, Iris E.; Leong, Wei; Tang, Jun; Gianella, Anita; Mieszawska, Aneta J.; Fay, Francois; Ma, Ge; Russell, Stewart; Callo, Catherine B.; Gordon, Ronald E.; Korkmaz, Emine; Post, Jan Andries; Zhao, Yiming; Gerritsen, Hans C.; Thran, Axel; Proksa, Roland; Daerr, Heiner; Storm, Gert; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.; Cormode, David P.

2013-01-01

Low-density lipoprotein (LDL) plays a critical role in cholesterol transport and is closely linked to the progression of several diseases. This motivates the development of methods to study LDL behavior from the microscopic to whole-body level. We have developed an approach to efficiently load LDL

Glycated albumin and direct low density lipoprotein cholesterol levels in type 2 diabetes mellitus

Science.gov (United States)

Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the ut...

Enzymatic Modification of Plasma Low Density Lipoproteins in Rabbits: A Potential Treatment for Hypercholesterolemia

Science.gov (United States)

Labeque, Regine; Mullon, Claudy J. P.; Ferreira, Joao Paulo M.; Lees, Robert S.; Langer, Robert

1993-04-01

Phospholipase A_2 (EC 3.1.1.4) hydrolyzes certain phospholipids of low density lipoprotein (LDL). Plasma clearance of phospholipase A_2-modified human LDL is up to 17 times faster than that of native human LDL in hypercholesterolemic rabbits. Modification of blood lipoproteins of hypercholesterolemic rabbits was performed by using an extracorporeal circuit containing immobilized phospholipase A_2. After 90-min treatments, nearly 30% decreases in plasma cholesterol concentrations were observed. Erythrocyte, leukocyte, and platelet counts showed no net change after treatment. This technique does not require any fluid replacement or sorbent regeneration and offers a potential approach for lowering serum cholesterol and LDL levels.

Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein-Mediated Reverse Cholesterol Transport

NARCIS (Netherlands)

Annema, Wijtske; Tietge, Uwe J. F.

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall

High density lipoproteins as indicators of endothelial dysfunction in children with diadetes type I

Directory of Open Access Journals (Sweden)

Lobanova S.M.

2011-12-01

Full Text Available The aim of the investigation was to study the level of blood high density lipoproteins (HDL in the groups of children with different course of diadetes type I in order to find out the dependence of course and complications of diabetes on that level. Materials and methods: Blood high density lipoprotein (HDL levels were investigated in children and adolescents with diadetes type I, depending on the duration of diadetes type I, age, stage of sexual development, the stage of diabetic nephropathy and levels of plasma endothelin-1 (E-1. Results: Decrease in HDL level with increasing duration of diadetes type I in prepubertate patients, higher indices of HDL cholesterol were determined in girls, especially with impaired puberty. HDL cholesterol was higher in diabetic nephropathy at the stage of proteinuria and high level of blood endothelin-1. Conclusion: The revealed changes were considered to cause deregulation of vascular endothelium as a manifestation of the initial stages of endothelial dysfunction

Levels of high-density lipoprotein cholesterol (HDL-C among children with steady-state sickle cell disease

Directory of Open Access Journals (Sweden)

Seixas Magda O

2010-08-01

Full Text Available Abstract Background The search for sickle cell disease (SCD prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis. Methods We prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records. Results Of the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P Conclusions We hypothesize that some SCD patients can have a specific dyslipidemic subphenotype characterized by low HDL-C with hypertriglyceridemia and high VLDL-C in association with other biomarkers, including those related to inflammation. This represents an important step toward a more reliable clinical prognosis. Additional studies are warranted to test this hypothesis and the probably mechanisms involved in this complex network of markers and their role in SCD pathogenesis.

Metabolism of triglyceride-rich nascent rat hepatic high density lipoproteins

International Nuclear Information System (INIS)

Winkler, K.E.; Marsh, J.B.

1989-01-01

Nascent high density lipoprotein (HDL) and nascent very low density lipoprotein (VLDL) were isolated from rat livers that had been perfused with [3H]glycerol to label the triglyceride. When injected into intact rats, the labeled HDL-triglyceride disappeared as rapidly as the VLDL-triglyceride, with only 10% of the injected label remaining in the plasma after 30 min. The protein moiety of nascent HDL was labeled with [35S]methionine in a similar fashion and the labeled nascent HDL was separated into nonretained (NR) and retained (R) fractions by heparin-Sepharose affinity chromatography. When injected into rats, 55% of the injected label in nascent fraction NR and 72% of that in nascent fraction R was recovered from plasma at 30 min, compared to only 10% of the triglyceride label from unfractionated nascent HDL, indicating dissociation of triglyceride and apolipoprotein clearance. The plasma decay curves for both triglyceride and protein were biexponential. By 5 min, 15% of the 35S label remaining in plasma represented apoE and apoC that had been transferred from nascent HDL fractions NR and R to the d less than 1.063 g/ml fraction of plasma. Plasma HDL was labeled in vivo with [35S]methionine, separated into fractions NR and R, and the clearance of the two plasma HDL fractions was compared with that of the corresponding nascent HDL fractions. Except for a faster rate of removal of the nascent HDL fractions during the first 5 min, the serum decay curves were very similar

High-Density Lipoproteins-Associated Proteins and Subspecies Related to Arterial Stiffness in Young Adults with Type 2 Diabetes Mellitus

Directory of Open Access Journals (Sweden)

Xiaoting Zhu

2018-01-01

Full Text Available Lower plasma levels of high-density lipoproteins (HDL in adolescents with type 2 diabetes (T2D have been associated with a higher pulse wave velocity (PWV, a marker of arterial stiffness. Evidence suggests that HDL proteins or particle subspecies are altered in T2D and these may drive these relationships. In this work, we set out to reveal any specific proteins and subspecies that are related to arterial stiffness in youth with T2D from proteomics data. Plasma and PWV measurements were previously acquired from lean and T2D adolescents. Each plasma sample was separated into 18 fractions and evaluated by mass spectrometry. Then, we applied a validated network-based computational approach to reveal HDL subspecies associated with PWV. Among 68 detected phospholipid-associated proteins, we found that seven were negatively correlated with PWV, indicating that they may be atheroprotective. Conversely, nine proteins show positive correlation with PWV, suggesting that they may be related to arterial stiffness. Intriguingly, our results demonstrate that apoA-I and histidine-rich glycoprotein may reverse their protective roles and become antagonistic in the setting of T2D. Furthermore, we revealed two arterial stiffness-associated HDL subspecies, each of which contains multiple PWV-related proteins. Correlation and disease association analyses suggest that these HDL subspecies might link T2D to its cardiovascular-related complications.

Apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular disease [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Michael D. Shapiro

2017-02-01

Full Text Available Cholesterol-rich, apolipoprotein B (apoB-containing lipoproteins are now widely accepted as the most important causal agents of atherosclerotic cardiovascular disease. Multiple unequivocal and orthogonal lines of evidence all converge on low-density lipoprotein and related particles as being the principal actors in the genesis of atherosclerosis. Here, we review the fundamental role of atherogenic apoB-containing lipoproteins in cardiovascular disease and several other humoral and parietal factors that are required to initiate and maintain arterial degeneration. The biology of foam cells and their interactions with high-density lipoproteins, including cholesterol efflux, are also briefly reviewed.

Relationship between low-density lipoprotein cholesterol and severe acute pancreatitis (“the lipid paradox”

Directory of Open Access Journals (Sweden)

Hong W

2018-05-01

Full Text Available Wandong Hong,1,* Vincent Zimmer,2,3,* Simon Stock,4,* Maddalena Zippi,5 Jones AQ Omoshoro-Jones,6 Mengtao Zhou71Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; 3Department of Medicine, Marienhausklinik St Josef Kohlhof, Neunkirchen, Germany; 4Department of Surgery, World Mate Emergency Hospital, Battambang, Cambodia; 5Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, Rome, Italy; 6Department of Surgery, Chris Hani-Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa; 7Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workBackground and aim: The aim of this study was to investigate the association between low-density lipoprotein cholesterol (LDL-C and the development of severe acute pancreatitis (SAP.Patients and methods: A total of 674 patients with acute pancreatitis were enrolled. Nonlinearity in the relationship between LDL-C and SAP was assessed by restricted cubic spline analysis. Univariable and multivariable regression analyses were used to identify independent risk factors of SAP.Results: The restricted cubic spline analysis suggested a nonlinear association between high-density lipoprotein cholesterol (HDL-C, LDL-C and triglyceride levels and incidence of SAP. The incidence of SAP in patients with low LDL-C (<90 mg/dL, moderate LDL-C (90–150 mg/dL and high LDL-C (>150 mg/dL levels was 15.1%, 3.7% and 9.8%, respectively. Multivariable analysis confirmed that low LDL-C levels (odds ratio [OR] 3.05; 95% confidence interval [CI] 1.35–6.90, high LDL-C levels (OR 4.42; 95% CI 1.41–13.87 and low HDL-C levels (OR 6.90; 95% CI 2.61–18.23 but

Langmuir-Blodgett films of polyaniline for low density lipoprotein detection

Energy Technology Data Exchange (ETDEWEB)

Matharu, Zimple [Department of Science and Technology Centre on Biomolecular Electronics, Biomedical Instrumentation Section, National Physical Laboratory (CSIR), Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Department of Physics and Astrophysics, University of Delhi, Delhi-110007 (India); Sumana, G. [Department of Science and Technology Centre on Biomolecular Electronics, Biomedical Instrumentation Section, National Physical Laboratory (CSIR), Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Gupta, Vinay [Department of Physics and Astrophysics, University of Delhi, Delhi-110007 (India); Malhotra, B.D., E-mail: bansi.malhotra@gmail.co [Department of Science and Technology Centre on Biomolecular Electronics, Biomedical Instrumentation Section, National Physical Laboratory (CSIR), Dr. K. S. Krishnan Marg, New Delhi-110012 (India)

2010-11-30

Langmuir-Blodgett (LB) films of polyaniline (PANI) were utilized for the fabrication of impedimetric immunosensor for detection of human plasma low density lipoprotein (LDL) by immobilizing anti-apolipoprotein B (AAB) via EDC-NHS coupling. The modified electrodes were characterized by electrochemical impedance spectroscopy (EIS) and scanning electron microscopy. AAB/PANI-SA LB immunoelectrodes studied by EIS spectroscopy revealed detection of LDL in the wide range of 0.018 {mu}M (6 mg/dl) to 0.39 {mu}M (130 mg/dl), covering the physiological range in blood, with a sensitivity of 11.25 k{Omega} {mu}M{sup -1}.

Langmuir-Blodgett films of polyaniline for low density lipoprotein detection

International Nuclear Information System (INIS)

Matharu, Zimple; Sumana, G.; Gupta, Vinay; Malhotra, B.D.

2010-01-01

Langmuir-Blodgett (LB) films of polyaniline (PANI) were utilized for the fabrication of impedimetric immunosensor for detection of human plasma low density lipoprotein (LDL) by immobilizing anti-apolipoprotein B (AAB) via EDC-NHS coupling. The modified electrodes were characterized by electrochemical impedance spectroscopy (EIS) and scanning electron microscopy. AAB/PANI-SA LB immunoelectrodes studied by EIS spectroscopy revealed detection of LDL in the wide range of 0.018 μM (6 mg/dl) to 0.39 μM (130 mg/dl), covering the physiological range in blood, with a sensitivity of 11.25 kΩ μM -1 .

Achieving secondary prevention low-density lipoprotein particle concentration goals using lipoprotein cholesterol-based data.

Directory of Open Access Journals (Sweden)

Simon C Mathews

Full Text Available BACKGROUND: Epidemiologic studies suggest that LDL particle concentration (LDL-P may remain elevated at guideline recommended LDL cholesterol goals, representing a source of residual risk. We examined the following seven separate lipid parameters in achieving the LDL-P goal of <1000 nmol/L goal for very high risk secondary prevention: total cholesterol to HDL cholesterol ratio, TC/HDL, <3; a composite of ATP-III very high risk targets, LDL-C<70 mg/dL, non-HDL-C<100 mg/dL and TG<150 mg/dL; a composite of standard secondary risk targets, LDL-C<100, non-HDL-C<130, TG<150; LDL phenotype; HDL-C ≥ 40; TG<150; and TG/HDL-C<3. METHODS: We measured ApoB, ApoAI, ultracentrifugation lipoprotein cholesterol and NMR lipoprotein particle concentration in 148 unselected primary and secondary prevention patients. RESULTS: TC/HDL-C<3 effectively discriminated subjects by LDL-P goal (F = 84.1, p<10(-6. The ATP-III very high risk composite target (LDL-C<70, nonHDL-C<100, TG<150 was also effective (F = 42.8, p<10(-5. However, the standard secondary prevention composite (LDL-C<100, non-HDL-C<130, TG<150 was also effective but yielded higher LDL-P than the very high risk composite (F = 42.0, p<10(-5 with upper 95% confidence interval of LDL-P less than 1000 nmol/L. TG<150 and TG/HDL-C<3 cutpoints both significantly discriminated subjects but the LDL-P upper 95% confidence intervals fell above goal of 1000 nmol/L (F = 15.8, p = 0.0001 and F = 9.7, p = 0.002 respectively. LDL density phenotype neared significance (F = 2.85, p = 0.094 and the HDL-C cutpoint of 40 mg/dL did not discriminate (F = 0.53, p = 0.47 alone or add discriminatory power to ATP-III targets. CONCLUSIONS: A simple composite of ATP-III very high risk lipoprotein cholesterol based treatment targets or TC/HDL-C ratio <3 most effectively identified subjects meeting the secondary prevention target level of LDL-P<1000 nmol/L, providing a potential alternative to advanced lipid testing in many clinical

Isolation and characterization of rhamnose-binding lectins from eggs of steelhead trout (Oncorhynchus mykiss) homologous to low density lipoprotein receptor superfamily.

Science.gov (United States)

Tateno, H; Saneyoshi, A; Ogawa, T; Muramoto, K; Kamiya, H; Saneyoshi, M

1998-07-24

methodology to investigate the interactions between STL2 and major egg yolk proteins from steelhead trout, lipovitellin, and beta'-component, which are known as vitellogenin digests. Interestingly, STL2 showed distinct interactions with both egg yolk proteins. The estimated values for the affinity constant (Ka) of STL2 to lipovitellin and beta' component were 3.44 x 10(6) and 4.99 x 10(6), respectively. These results suggest that the fish egg lectins belong to a new family of animal lectin structurally related to the low density lipoprotein receptor super- family.

Determining the risk of cardiovascular disease using ion mobility of lipoproteins

Science.gov (United States)

Benner, W. Henry; Krauss, Ronald M.; Blanche, Patricia J.

2010-05-11

A medical diagnostic method and instrumentation system for analyzing noncovalently bonded agglomerated biological particles is described. The method and system comprises: a method of preparation for the biological particles; an electrospray generator; an alpha particle radiation source; a differential mobility analyzer; a particle counter; and data acquisition and analysis means. The medical device is useful for the assessment of human diseases, such as cardiac disease risk and hyperlipidemia, by rapid quantitative analysis of lipoprotein fraction densities. Initially, purification procedures are described to reduce an initial blood sample to an analytical input to the instrument. The measured sizes from the analytical sample are correlated with densities, resulting in a spectrum of lipoprotein densities. The lipoprotein density distribution can then be used to characterize cardiac and other lipid-related health risks.

Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study.

Science.gov (United States)

Rao, Fangwen; Schork, Andrew J; Maihofer, Adam X; Nievergelt, Caroline M; Marcovina, Santica M; Miller, Elizabeth R; Witztum, Joseph L; O'Connor, Daniel T; Tsimikas, Sotirios

2015-07-01

To determine whether biomarkers of oxidized lipoproteins are genetically determined. Lipoprotein(a) (Lp[a]) is a heritable risk factor and carrier of oxidized phospholipids (OxPL). We measured oxidized phospholipids on apolipoprotein B-containing lipoproteins (OxPL-apoB), Lp(a), IgG, and IgM autoantibodies to malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes in 386 monozygotic and dizygotic twins to estimate trait heritability (h(2)) and determine specific genetic effects among traits. A genome-wide linkage study followed by genetic association was performed. The h(2) (scale: 0-1) for Lp(a) was 0.91±0.01 and for OxPL-apoB 0.87±0.02, which were higher than physiological, inflammatory, or lipid traits. h(2) of IgM malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes were 0.69±0.04, 0.67±0.05, and 0.80±0.03, respectively, and for IgG malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes 0.62±0.05, 0.52±0.06, and 0.53±0.06, respectively. There was an inverse correlation between the major apo(a) isoform and OxPL-apoB (R=-0.49; Plipoprotein and copper oxidized low-density lipoprotein, and apoB-immune complexes. Sib-pair genetic linkage of the Lp(a) trait revealed that single nucleotide polymorphism rs10455872 was significantly associated with OxPL-apoB after adjusting for Lp(a). OxPL-apoB and other biomarkers of oxidized lipoproteins are highly heritable cardiovascular risk factors that suggest novel genetic origins of atherothrombosis. © 2015 American Heart Association, Inc.

Effects of MAT9001 containing eicosapentaenoic acid and docosapentaenoic acid, compared to eicosapentaenoic acid ethyl esters, on triglycerides, lipoprotein cholesterol, and related variables.

Science.gov (United States)

Maki, Kevin C; Bobotas, George; Dicklin, Mary R; Huebner, Margie; Keane, William F

Long-chain omega-3 fatty acid concentrate pharmaceuticals are used in the United States for treatment of severe hypertriglyceridemia (≥500 mg/dL) and are under investigation as adjuncts to statins for lowering cardiovascular risk in patients with high triglycerides (TGs; 200-499 mg/dL). To evaluate MAT9001, an investigational prescription-only omega-3 fatty acid agent containing predominantly eicosapentaenoic acid (EPA) and docosapentaenoic acid, in 42 men and women with fasting TG 200 to 400 mg/dL. In this open-label, crossover trial, subjects received MAT9001 and EPA ethyl esters (EPA-EE) in random order. They were housed in a clinical research unit for 2 14-day treatment periods, separated by a ≥35-day washout. Lipoprotein lipids, apolipoproteins (Apos) and proprotein convertase subtilisin kexin type 9 levels were measured before and at the end of each treatment period. MAT9001, compared with EPA-EE, resulted in significantly (P < .05) larger reductions from pretreatment levels for TG (-33.2% vs -10.5%), total cholesterol (-9.0% vs -6.2%), non-high-density lipoprotein cholesterol (-8.8% vs -4.6%), very low-density lipoprotein cholesterol (-32.5% vs -8.1%), Apo C3 (-25.5% vs -5.0%), and proprotein convertase subtilisin kexin type 9 (-12.3% vs +8.8%). MAT9001 also produced a significantly (P = .003) larger reduction in Apo A1 (-15.3% vs -10.2%), but responses for high-density lipoprotein cholesterol (-11.3% vs -11.1%), low-density lipoprotein cholesterol (-2.4% vs -4.3%), and Apo B (-3.8% vs -0.7%), respectively, were not significantly different relative to EPA-EE. MAT9001 produced significantly larger reductions than EPA-EE in several lipoprotein-related variables that would be expected to favorably alter cardiovascular disease risk in men and women with hypertriglyceridemia. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Release of endothelial cell lipoprotein lipase by plasma lipoproteins and free fatty acids

International Nuclear Information System (INIS)

Saxena, U.; Witte, L.D.; Goldberg, I.J.

1989-01-01

Lipoprotein lipase (LPL) bound to the lumenal surface of vascular endothelial cells is responsible for the hydrolysis of triglycerides in plasma lipoproteins. Studies were performed to investigate whether human plasma lipoproteins and/or free fatty acids would release LPL which was bound to endothelial cells. Purified bovine milk LPL was incubated with cultured porcine aortic endothelial cells resulting in the association of enzyme activity with the cells. When the cells were then incubated with media containing chylomicrons or very low density lipoproteins (VLDL), a concentration-dependent decrease in the cell-associated LPL enzymatic activity was observed. In contrast, incubation with media containing low density lipoproteins or high density lipoproteins produced a much smaller decrease in the cell-associated enzymatic activity. The addition of increasing molar ratios of oleic acid:bovine serum albumin to the media also reduced enzyme activity associated with the endothelial cells. To determine whether the decrease in LPL activity was due to release of the enzyme from the cells or inactivation of the enzyme, studies were performed utilizing radioiodinated bovine LPL. Radiolabeled LPL protein was released from endothelial cells by chylomicrons, VLDL, and by free fatty acids (i.e. oleic acid bound to bovine serum albumin). The release of radiolabeled LPL by VLDL correlated with the generation of free fatty acids from the hydrolysis of VLDL triglyceride by LPL bound to the cells. Inhibition of LPL enzymatic activity by use of a specific monoclonal antibody, reduced the extent of release of 125 I-LPL from the endothelial cells by the added VLDL. These results demonstrated that LPL enzymatic activity and protein were removed from endothelial cells by triglyceride-rich lipoproteins (chylomicrons and VLDL) and oleic acid

β-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins

Directory of Open Access Journals (Sweden)

Khan Tayeba

2004-11-01

Full Text Available Abstract Background Recent studies suggest that hypercholesterolemia, an established risk factor for atherosclerosis, is also a risk factor for Alzheimer's disease. The myeloid scavenger receptor CD36 binds oxidized lipoproteins that accumulate with hypercholesterolemia and mediates their clearance from the circulation and peripheral tissues. Recently, we demonstrated that CD36 also binds fibrillar β-amyloid and initiates a signaling cascade that regulates microglial recruitment and activation. As increased lipoprotein oxidation and accumulation of lipid peroxidation products have been reported in Alzheimer's disease, we investigated whether β-amyloid altered oxidized lipoprotein clearance via CD36. Methods The availability of mice genetically deficient in class A (SRAI & II and class B (CD36 scavenger receptors has facilitated studies to discriminate their individual actions. Using primary microglia and macrophages, we assessed the impact of Aβ on: (a cholesterol ester accumulation by GC-MS and neutral lipid staining, (b binding, uptake and degradation of 125I-labeled oxidized lipoproteins via CD36, SR-A and CD36/SR-A-independent pathways, (c expression of SR-A and CD36. In addition, using mice with targeted deletions in essential kinases in the CD36-signaling cascade, we investigated whether Aβ-CD36 signaling altered metabolism of oxidized lipoproteins. Results In primary microglia and macrophages, Aβ inhibited binding, uptake and degradation of oxidized low density lipoprotein (oxLDL in a dose-dependent manner. While untreated cells accumulated abundant cholesterol ester in the presence of oxLDL, cells treated with Aβ were devoid of cholesterol ester. Pretreatment of cells with Aβ did not affect subsequent degradation of oxidized lipoproteins, indicating that lysosomal accumulation of Aβ did not disrupt this degradation pathway. Using mice with targeted deletions of the scavenger receptors, we demonstrated that Aβ inhibited oxidized

Cholesterol synthesis by human fetal hepatocytes: effect of lipoproteins

International Nuclear Information System (INIS)

Carr, B.R.; Simpson, E.R.

1984-01-01

The purpose of the present investigation was to determine the effect of various lipoproteins on the rate of cholesterol synthesis of human fetal liver cells maintained in culture. This was accomplished by measuring the rate of incorporation of tritium from tritiated water or carbon 14-labeled acetate into cholesterol in human fetal liver cells. Optimal conditions for each assay were determined. When human fetal liver cells were maintained in the presence of low-density lipoprotein, cholesterol synthesis was inhibited in a concentration-dependent fashion. Intermediate--density lipoprotein and very-low-density lipoprotein also suppressed cholesterol synthesis in human fetal liver cells. In contrast, high-density lipoprotein stimulated cholesterol synthesis in human fetal liver cells. The results of the present as well as our previous investigations suggest that multiple interrelationships exist between fetal liver cholesterol synthesis and lipoprotein-cholesterol utilization by the human fetal adrenal gland and that these processes serve to regulate the lipoprotein-cholesterol levels in fetal plasma

Hepatitis C Virus, Cholesterol and Lipoproteins — Impact for the Viral Life Cycle and Pathogenesis of Liver Disease

Science.gov (United States)

Felmlee, Daniel J.; Hafirassou, Mohamed Lamine; Lefevre, Mathieu; Baumert, Thomas F.; Schuster, Catherine

2013-01-01

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects. PMID:23698400

Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling.

Science.gov (United States)

Vogel, Megan E; Idelman, Gila; Konaniah, Eddy S; Zucker, Stephen D

2017-04-01

Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice and elucidate the molecular processes underlying this effect. Bilirubin, at physiological concentrations (≤20 μmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to Ldlr -/- mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression. Bilirubin suppresses atherosclerotic plaque formation in Ldlr -/- mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin. © 2017 The Authors. Published on behalf of the American Heart Association, Inc

Identification of the receptor scavenging hemopexin-heme complexes

DEFF Research Database (Denmark)

Hvidberg, Vibeke; Maniecki, Maciej B; Jacobsen, Christian

2005-01-01

and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons......, and syncytiotrophoblasts. Binding experiments, including Biacore analysis, showed that hemopexin-heme complex formation elicits the high receptor affinity. Uptake studies of radio-labeled hemopexin-heme complex in LRP/CD91-expressing COS cells and confocal microscopy of the cellular processing of fluorescent hemopexin......-heme complexes are removed by a receptor-mediated pathway showing striking similarities to the CD163-mediated haptoglobin-hemoglobin clearance in macrophages. Furthermore, the data indicate a hitherto unknown role of LRP/CD91 in inflammation....

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Science.gov (United States)

Chapman, M. John; Ginsberg, Henry N.; Amarenco, Pierre; Andreotti, Felicita; Borén, Jan; Catapano, Alberico L.; Descamps, Olivier S.; Fisher, Edward; Kovanen, Petri T.; Kuivenhoven, Jan Albert; Lesnik, Philippe; Masana, Luis; Nordestgaard, Børge G.; Ray, Kausik K.; Reiner, Zeljko; Taskinen, Marja-Riitta; Tokgözoglu, Lale; Tybjærg-Hansen, Anne; Watts, Gerald F.

2011-01-01

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. PMID:21531743

The majority of lipoprotein lipase in plasma is bound to remnant lipoproteins: A new definition of remnant lipoproteins.

Science.gov (United States)

Sato, Koichi; Okajima, Fumikazu; Miyashita, Kazuya; Imamura, Shigeyuki; Kobayashi, Junji; Stanhope, Kimber L; Havel, Peter J; Machida, Tetsuo; Sumino, Hiroyuki; Murakami, Masami; Schaefer, Ernst; Nakajima, Katsuyuki

2016-10-01

Lipoprotein lipase (LPL) is a multifunctional protein and a key enzyme involved in the regulation of lipoprotein metabolism. We determined the lipoproteins to which LPL is bound in the pre-heparin and post-heparin plasma. Tetrahydrolipstatin (THL), a potent inhibitor of serine lipases, was used to block the lipolytic activity of LPL, thereby preventing changes in the plasma lipoproteins due to ex vivo lipolysis. Gel filtration was performed to obtain the LPL elution profiles in plasma and the isolated remnant lipoproteins (RLP). When ex vivo lipolytic activity was inhibited by THL in the post-heparin plasma, majority of the LPL was found in the VLDL elution range, specifically in the RLP as inactive dimers. However, in the absence of THL, most of the LPL was found in the HDL elution range as active dimers. Furthermore, majority of the LPL in the pre-heparin plasma was found in the RLP as inactive form, with broadly diffused lipoprotein profiles in the presence and absence of THL. It is suggested that during lipolysis in vivo, the endothelial bound LPL dimers generates RLP, forming circulating RLP-LPL complexes in an inactive form that subsequently binds and initiates receptor-mediated catabolism. Copyright © 2016 Elsevier B.V. All rights reserved.

Unique Features of High-Density Lipoproteins in the Japanese: In Population and in Genetic Factors

Directory of Open Access Journals (Sweden)

Shinji Yokoyama

2015-04-01

Full Text Available Despite its gradual increase in the past several decades, the prevalence of atherosclerotic vascular disease is low in Japan. This is largely attributed to difference in lifestyle, especially food and dietary habits, and it may be reflected in certain clinical parameters. Plasma high-density lipoprotein (HDL levels, a strong counter risk for atherosclerosis, are indeed high among the Japanese. Accordingly, lower HDL seems to contribute more to the development of coronary heart disease (CHD than an increase in non-HDL lipoproteins at a population level in Japan. Interestingly, average HDL levels in Japan have increased further in the past two decades, and are markedly higher than in Western populations. The reasons and consequences for public health of this increase are still unknown. Simulation for the efficacy of raising HDL cholesterol predicts a decrease in CHD of 70% in Japan, greater than the extent by reducing low-density lipoprotein cholesterol predicted by simulation or achieved in a statin trial. On the other hand, a substantial portion of hyperalphalipoproteinemic population in Japan is accounted for by genetic deficiency of cholesteryl ester transfer protein (CETP, which is also commonly unique in East Asian populations. It is still controversial whether CETP mutations are antiatherogenic. Hepatic Schistosomiasis is proposed as a potential screening factor for historic accumulation of CETP deficiency in East Asia.

Heparin induces an accumulation of atherogenic lipoproteins during hemodialysis in normolipidemic end-stage renal disease patients.

Science.gov (United States)

Barbagallo, Carlo M; Noto, Davide; Cefalù, Angelo B; Ganci, Antonia; Giammarresi, Carlo; Panno, Donata; Cusumano, Gaspare; Greco, Massimiliano; Di Gaudio, Francesca; Averna, Maurizio R

2015-07-01

Dyslipidemias may account for the excess of cardiovascular mortality in end-stage renal disease (ESRD). Lipoprotein studies in ESRD patients are usually relative to prehemodialysis samples even if significative changes may occur after dialysis. In this study, we aimed to investigate the effects of ESRD on triglyceride-rich lipoproteins (TRL) subpopulations distribution and acute change following hemodialytic procedures, including the relative contribution of heparin administration. We selected a group of normolipidemic male middle-aged ESRD patients free of any concomitant disease affecting lipoprotein remnant metabolism compared with controls. We separated TRL subfractions according to density and apoE content and evaluated the changes of these particles after hemodialytic procedures with or without heparin. ESRD subjects had higher TRL subfractions, with the exception of apoE-rich particles, lower high-density lipoprotein (HDL) largest subclasses, and a smaller low-density lipoprotein peak particle size than controls. After a hemodialytic standard procedure with heparin, we demonstrated a significant reduction of triglyceride, an increase of HDL-cholesterol levels, and a raise of small very-low-density lipoprotein, intermediate-density lipoproteins (IDL), apoE-rich particles, and non-HDL-cholesterol levels. When hemodialysis was performed without heparin, no significant changes were observed. In the absence of concomitant hyperlipidemic triggers, ESRD patients show significant lipoprotein abnormalities before dialysis, but without any increased remnant particles concentrations. We speculate that hemodialysis, in particular heparin administration during this procedure, leads to a massive atherogenic TRLs production because of the acute stimulation of the dysfunctional lipolytic system not followed by an efficient removal, determining a recurrent lipoprotein remnant accumulation. © 2014 International Society for Hemodialysis.

Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia

NARCIS (Netherlands)

Bredie, S. J.; Westerveld, H. T.; Knipscheer, H. C.; de Bruin, T. W.; Kastelein, J. J.; Stalenhoef, A. F.

1996-01-01

Familial combined hyperlipidaemia (FCH), characterized by elevated very-low-density lipoprotein (VLDL) and/or low-density lipoprotein (LDL), is associated with an increased prevalence of premature cardiovascular disease. Therefore, lipid-lowering is frequently indicated. We evaluated in a parallel,

Novel changes in discoidal high density lipoprotein morphology: a molecular dynamics study.

Science.gov (United States)

Catte, Andrea; Patterson, James C; Jones, Martin K; Jerome, W Gray; Bashtovyy, Denys; Su, Zhengchang; Gu, Feifei; Chen, Jianguo; Aliste, Marcela P; Harvey, Stephen C; Li, Ling; Weinstein, Gilbert; Segrest, Jere P

2006-06-15

ApoA-I is a uniquely flexible lipid-scavenging protein capable of incorporating phospholipids into stable particles. Here we report molecular dynamics simulations on a series of progressively smaller discoidal high density lipoprotein particles produced by incremental removal of palmitoyloleoylphosphatidylcholine via four different pathways. The starting model contained 160 palmitoyloleoylphosphatidylcholines and a belt of two antiparallel amphipathic helical lipid-associating domains of apolipoprotein (apo) A-I. The results are particularly compelling. After a few nanoseconds of molecular dynamics simulation, independent of the starting particle and method of size reduction, all simulated double belts of the four lipidated apoA-I particles have helical domains that impressively approximate the x-ray crystal structure of lipid-free apoA-I, particularly between residues 88 and 186. These results provide atomic resolution models for two of the particles produced by in vitro reconstitution of nascent high density lipoprotein particles. These particles, measuring 95 angstroms and 78 angstroms by nondenaturing gradient gel electrophoresis, correspond in composition and in size/shape (by negative stain electron microscopy) to the simulated particles with molar ratios of 100:2 and 50:2, respectively. The lipids of the 100:2 particle family form minimal surfaces at their monolayer-monolayer interface, whereas the 50:2 particle family displays a lipid pocket capable of binding a dynamic range of phospholipid molecules.

Low-density lipoprotein cholesterol is associated with fracture risk in diabetes patients - a nested case-control study

DEFF Research Database (Denmark)

Starup-Linde, Jakob; Gregersen, Søren; Vestergaard, Peter

2014-01-01

available for an analysis of patient characteristics, co-morbidities, biochemical parameters and drug usage. Results: Patient age at the time of diabetes diagnosis, a diagnosis of previous fracture, an alcohol related diagnosis, total cholesterol level, and the usage of antidepressants, antiepileptics...... and insulin all increased the odds of fracture. Low-density lipoprotein cholesterol (LDL) levels decreased the odds of fracture, where the level of 3.04-5.96 mmol/l was optimal with regard to fracture risk. Conclusion: LDL may add to the understanding of fractures in diabetes patients and it may be added...

High-Density Lipoprotein Cholesterol Level Relates to Working Memory, Immediate and Delayed Cued Recall in Brazilian Older Adults: The Role of Cognitive Reserve.

Science.gov (United States)

Ihle, Andreas; Gouveia, Élvio R; Gouveia, Bruna R; Freitas, Duarte L; Jurema, Jefferson; Tinôco, Maria A; Kliegel, Matthias

2017-01-01

The present study set out to investigate the relation of the high-density lipoprotein cholesterol (HDL-C) level to cognitive performance and its interplay with key markers of cognitive reserve in a large sample of older adults. We assessed tests of working memory, immediate and delayed cued recall in 701 older adults from Amazonas, Brazil. The HDL-C level was derived from fasting blood samples. In addition, we interviewed individuals on their education, past occupation, and cognitive leisure activity. A critically low HDL-C level (cued recall. Moderation analyses suggested that the relations of the HDL-C level to working memory and delayed cued recall were negligible in individuals with longer education, a higher cognitive level of the job, and greater engagement in cognitive leisure activity. Cognitive reserve accumulated during the life course may reduce the detrimental influences of a critically low HDL-C level on cognitive functioning in old age. © 2017 S. Karger AG, Basel.

Lipoprotein (a) and biochemical parameters in elderly

OpenAIRE

Yuttana Sudjaroen

2016-01-01

Background: Lipoprotein (a) [Lp(a)] is an low-density lipoprotein like particle and is an important independent risk factor for coronary artery diseases (CAD). Few studies on Lp(a) level in Thai elderly to screening risk of CAD may concerned. Aims: To study the relation of Lp(a) level and routine biochemical parameters including lipid profiles and fasting blood glucose in elderly and to determine risk of subclinical symptoms by using Lp(a) levels as early risk predictor. Settings and Design: ...

Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Blood Pressure as Mediators From Obesity to Ischemic Heart Disease

DEFF Research Database (Denmark)

Varbo, Anette; Benn, Marianne; Smith, George Davey

2015-01-01

RATIONALE: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se. OBJECTIVE: To test the hypothesis that the increased IHD risk because of obesity is mediated through...... variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood...... obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively. CONCLUSIONS: The increased IHD risk because...

Low-Density Lipoproteins Oxidation and Endometriosis

Directory of Open Access Journals (Sweden)

Grzegorz Polak

2013-01-01

Full Text Available The etiopathogenesis of endometriosis still remains unknown. Recent data provide new valuable information concerning the role of oxidative stress in the pathophysiology of the disease. It has been proved that levels of different lipid peroxidation end products are increased in both peritoneal fluid (PF and serum of endometriotic patients. We assessed the concentration of oxidized low-density lipoproteins (oxLDL in PF of 110 women with different stages of endometriosis and 119 women with serous ( or dermoid ( ovarian cysts, as the reference groups. PF oxLDL levels were evaluated by ELISA. We found that concentrations of oxLDL in PF of endometriotic women were significantly higher compared to women with serous but not dermoid ovarian cysts. Interestingly, by analyzing concentrations of oxLDL in women with different stages of the disease, it was noted that they are significantly higher only in the subgroup of patients with stage IV endometriosis as compared to women with ovarian serous cysts. In case of minimal, mild, and moderate disease, PF oxLDL levels were similar to those noted in reference groups. Our results indicate that disrupted oxidative status in the peritoneal cavity of women with endometriosis may play a role in the pathogenesis of advanced stages of the disease.

Comparing fluorescence-based cell-free assays for the assessment of antioxidative capacity of high-density lipoproteins

Science.gov (United States)

Background: Population studies have shown an inverse association between high-density lipoprotein (HDL) cholesterol levels and risk of coronary heart disease (CHD). HDL has different functions, including the ability to protect biological molecules from oxidation. Our aim was to evaluate the performa...

Characteristics of 2,4,5,2',4',5'-hexachlorobiphenyl distribution among lipoproteins in vitro

International Nuclear Information System (INIS)

Vomachka, M.S.; Vodicnik, M.J.; Lech, J.J.

1983-01-01

The uptake, distribution, and transfer of 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) were examined in vitro with human and rat whole blood, plasma, and lipoprotein fractions. 6-CB distribution between plasma and erythrocytes as well as among lipoproteins was determined following sedimentation of erythrocytes and ultracentrifugal fractionation of plasma. In both rat and human whole blood, 70 to 75% of 6-CB partitioned into plasma and 25 to 30% into erythrocytes. The uptake of 6-CB into plasma was extremely rapid and the rate of uptake was found to be dependent upon temperature. The distribution of 6-CB among lipoproteins was relatively homogeneous with 20 to 30% being distributed in very low-density lipoproteins (VLDL, d . 0.95-1.006 g/ml), 15 to 20% in low-density lipoproteins (LDL, d . 1.006-1.063 g/ml), and 15 to 25% in high-density lipoproteins (HDL, d . 1.063-1.21 g/ml). Over 25% of 6-CB was found in the remaining bottom fraction. In addition, each isolated fraction when incubated alone with 6-CB was shown capable of uptake. The relative proportion of 6-CB among the lipoproteins was independent of the level taken up by plasma. 6-CB was also found to transfer among lipoproteins. This exchange of 6-CB proved to be dependent upon the concentrations of both protein and triacylglycerol in the incubations. Two proteins in the bottom fraction (Bf), albumin and a steroid binding globulin, were capable of competing with the lipoproteins for 6-CB uptake

Controlling for high-density lipoprotein cholesterol does not affect the magnitude of the relationship between alcohol and coronary heart disease.

Science.gov (United States)

Magnus, Per; Bakke, Eirin; Hoff, Dominic A; Høiseth, Gudrun; Graff-Iversen, Sidsel; Knudsen, Gun Peggy; Myhre, Ronny; Normann, Per Trygve; Næss, Øyvind; Tambs, Kristian; Thelle, Dag S; Mørland, Jørg

2011-11-22

This study tested the hypothesis that moderate alcohol intake exerts its cardioprotective effect mainly through an increase in the serum level of high-density lipoprotein cholesterol. In the Cohort of Norway (CONOR) study, 149 729 adult participants, recruited from 1994 to 2003, were followed by linkage to the Cause of Death Registry until 2006. At recruitment, questionnaire data on alcohol intake were collected, and the concentration of high-density lipoprotein cholesterol in serum was measured. Using Cox regression, we found that the adjusted hazard ratio for men for dying from coronary heart disease was 0.52 (95% confidence interval, 0.39-0.69) when consuming alcohol more than once a week compared with never or rarely. The ratio changed only slightly, to 0.55 (0.41-0.73), after the regression model included the serum level of high-density cholesterol. For women, the corresponding hazard ratios were 0.62 (0.32-1.23) and 0.68 (0.34-1.34), respectively. Alcohol intake is related to a reduced risk of death from coronary heart disease in the follow-up of a large, population-based Norwegian cohort study with extensive control for confounding factors. Our findings suggest that the serum level of high-density cholesterol is not an important intermediate variable in the possible causal pathway between moderate alcohol intake and coronary heart disease.

Analytic ultracentrifugation of lipoproteins: Some current collaborations

International Nuclear Information System (INIS)

Lindgren, F.T.

1987-01-01

This summary briefly reports on three ongoing studies - the heterogeneity of Low Density Lipoproteins (LDL) in the cynomolgus monkey, the domain nature of Apolipoprotein E-3, and the molecular weight of apoB-100 in low density lipoprotein subfractions in normal males. 4 refs

How Well Does BODIPY-Cholesteryl Ester Mimic Unlabeled Cholesteryl Esters in High Density Lipoprotein Particles?

DEFF Research Database (Denmark)

Karilainen, Topi; Vuorela, Timo; Vattulainen, Ilpo

2015-01-01

We compare the behavior of unlabeled and BODIPY-labeled cholesteryl ester (CE) in high density lipoprotein by atomistic molecular dynamics simulations. We find through replica exchange umbrella sampling and unbiased molecular dynamics simulations that BODIPY labeling has no significant effect...... on the partitioning of CE between HDL and the water phase. However, BODIPY-CE was observed to diffuse more slowly and locate itself closer to the HDL-water interface than CE due to the BODIPY probe that is constrained to the surface region, and because the CE body in BODIPY-CE prefers to align itself away from...... the HDL surface. The implications as to the suitability of BODIPY to explore lipoprotein properties are discussed....

Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma

Directory of Open Access Journals (Sweden)

Kuai R

2017-09-01

.115 µM, P<0.05. Fluorescent dye-loaded sHDL nanodisks efficiently accumulated in H295R adrenal carcinoma xenografts 24 hours following dosing. Moreover, daily intraperitoneal administration of 7 mg/kg WGA-TA-loaded sHDL nanodisks significantly inhibited tumor growth during 21-day administration to H295R xenograft-bearing mice compared to placebo (P<0.01. Collectively, these results suggest that WGA-TA-loaded nanodisks may represent a novel and beneficial therapeutic strategy for the treatment of ACC. Keywords: synthetic high-density lipoproteins, scavenger receptor class B1, targeted delivery, nanodisks, withalongolides, adrenocortical carcinomas

Low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio is the best surrogate marker for insulin resistance in non-obese Japanese adults

Directory of Open Access Journals (Sweden)

Takayama Shuzo

2010-12-01

Full Text Available Abstract Background The aim of the present study was to examine how lipid profiles are associated with insulin resistance in Japanese community-dwelling adults. Methods This cross-sectional study included 614 men aged 58 ± 14 (mean ± standard deviation; range, 20-89 years and 779 women aged 60 ± 12 (range, 21-88 years. The study sample were 1,042 (74.8% non-obese (BMI 2 and 351 (25.2% overweight (BMI ≥ 25 kg/m2 subjects. Insulin resistance was defined by homeostasis model assessment of insulin resistance (HOMA-IR of at least 2.5. The areas under the curve (AUC of the receiver operating characteristic curves (ROC were used to compare the power of these serum markers. Results In non-obese subjects, the best marker of insulin resistance was low-density lipoprotein cholesterol (LDL-C/high-density lipoprotein cholesterol (HDL-C ratio of 0.74 (95% confidence interval (CI, 0.66-0.80. The HDL-C, triglyceride (TG/HDL-C ratio, and non-HDL-C also discriminated insulin resistance, as the values for AUC were 0.31 (95% CI, 0.24-0.38, 0.69 (95% CI, 0.62-0.75 and 0.69 (95% CI, 0.62-0.75, respectively. In overweight subjects, the AUC for TG and TG/HDL-C ratio were 0.64 (0.58-0.71 and 0.64 (0.57-0.70, respectively. The optimal cut-off point to identifying insulin resistance for these markers yielded the following values: TG/HDL-C ratio of ≥1.50 and LDL-C/HDL-C ratio of ≥2.14 in non-obese subjects, and ≥2.20, ≥2.25 in overweight subjects. In non-obese subjects, the positive likelihood ratio was greatest for LDL-C/HDL-C ratio. Conclusion In non-obese Japanese adults, LDL-C/HDL-C ratio may be the best reliable marker of insulin resistance.

The Application of a Modified d-ROMs Test for Measurement of Oxidative Stress and Oxidized High-Density Lipoprotein

Directory of Open Access Journals (Sweden)

Fumiaki Ito

2017-02-01

Full Text Available Reactive oxygen species (ROS are involved in the initiation and progression of atherosclerosis. ROS-derived hydroperoxides, as an indicator of ROS production, have been measured by using the diacron reactive oxygen metabolites (d-ROMs test, which requires iron-containing transferrin in the reaction mixture. In this study we developed a modified d-ROMs test, termed the Fe-ROMs test, where iron ions were exogenously added to the reaction mixture. This modification is expected to exclude the assay variation that comes from different blood iron levels in individuals. In addition, this Fe-ROMs test was helpful for determining the class of plasma lipoproteins that are hydroperoxidized. Low-density lipoprotein/very low-density lipoprotein (LDL/VLDL and high-density lipoprotein (HDL were purified by use of an LDL/VLDL purification kit and the dextran sulfate-Mg2+ precipitation method, respectively; their hydroperoxide contents were assessed by performing the Fe-ROMs test. The majority of the hydroperoxides were detected only in the HDL fraction, not in the LDL/VLDL. Further detailed analysis of HDLs by size-exclusion high-performance liquid chromatography revealed that the hydroperoxide-containing molecules were small-sized HDLs. Because HDL was shown to be the principal vehicle for the plasma hydroperoxides, this Fe-ROMs test is a beneficial method for the assessment of oxidized-HDL levels. Indeed, Fe-ROMs levels were strongly associated with the levels of oxidized HDL, which were determined by performing the malondialdehyde-modified HDL enzyme immunoassay. In conclusion, the Fe-ROMs test using plasma itself or the HDL fraction after dextran sulfate-Mg2+ precipitation is useful to assess the functionality of HDL, because the oxidation of HDL impairs its antiatherogenic capacity.

Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits

DEFF Research Database (Denmark)

Nielsen, I. L. F.; Rasmussen, S.E.; Mortensen, Alicja

2005-01-01

a purified anthocyanin fraction front black currants, a black currant juice, probucol or control diet for 16 weeks. Purified anthocyanins significantly increased plasma cholesterol and low-density lipoprotein (LDL) cholesterol. Intake of black currant juice had no effect on total plasma cholesterol......, but lowered very-low-density lipoprotein (VLDL) cholesterol significantly. There were no significant effects of either purified anthocyanins or black currant juice on aortic cholesterol or development of atherosclerosis after 16 weeks. Probucol had no effect on plasma cholesterol but significantly lowered......, antioxidant enzymes, protein and lipid oxidation were not affected by any of the anthocyanin treatments. Adverse effects of purified anthocyanins were observed on plasma- and LDL-cholesterol. These effects were not observed with black currant juice, suggesting that black currants may contain components...

Sex, social status, and CRF receptor densities in naked mole-rats.

Science.gov (United States)

Beery, Annaliese K; Bicks, Lucy; Mooney, Skyler J; Goodwin, Nastacia L; Holmes, Melissa M

2016-02-01

Naked mole-rats (Heterocephalus glaber) live in groups that are notable for their large size and caste structure, with breeding monopolized by a single female and a small number of males. Recent studies have demonstrated substantial differences between the brains of breeders and subordinates induced by changes in social standing. Corticotropin-releasing factor (CRF) receptors-which bind the hormone CRF as well as related peptides-are important regulators of stress and anxiety, and are emerging as factors affecting social behavior. We conducted autoradiographic analyses of CRF1 and CRF2 receptor binding densities in female and male naked mole-rats varying in breeding status. Both globally and in specific brain regions, CRF1 receptor densities varied with breeding status. CRF1 receptor densities were higher in subordinates across brain regions, and particularly in the piriform cortex and cortical amygdala. Sex differences were present in CRF2 receptor binding densities, as is the case in multiple vole species. CRF2 receptor densities were higher in females, both globally and in the cortical amygdala and lateral amygdalar nucleus. These results provide novel insights into the neurobiology of social hierarchy in naked mole-rats, and add to a growing body of work that links changes in the CRF system with social behavior. © 2015 Wiley Periodicals, Inc.

Glycation and glycoxidation of low-density lipoproteins by glucose and low-molecular mass aldehydes. Formation of modified and oxidized particles

DEFF Research Database (Denmark)

Knott, Heather M; Brown, Bronwyn E; Davies, Michael Jonathan

2003-01-01

by the adduction of glucose or species derived from glucose, such as low-molecular mass aldehydes, to proteins. These reactions can be nonoxidative (glycation) or oxidative (glycoxidation) and result in the conversion of low-density lipoproteins (LDL) to a form that is recognized by the scavenger receptors...... with glucose. These processes are rapid and unaffected by low concentrations of copper ions. In contrast, lipid and protein oxidation are slow processes and occur to a limited extent in the absence of added copper ions. No evidence was obtained for the stimulation of lipid or protein oxidation by glucose...... or methylglyoxal in the presence of copper ions, whereas glycolaldehyde stimulated such reactions to a modest extent. These results suggest that the earliest significant events in this system are metal ion-independent glycation (modification) of the protein component of LDL, whilst oxidative events (glycoxidation...

Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions.

Science.gov (United States)

Godsland, I F; Wynn, V; Crook, D; Miller, N E

1987-12-01

We review the hypothesis that the incidence of coronary heart disease (CHD) is higher in men than in women due to differences in plasma lipoprotein risk factors between the sexes. Men and women appear to be equally susceptible to the effects of lipoprotein risk factors for CHD, and the difference between the sexes in lipoprotein risk factors for CHD appears to be consistent with their being, at least in part, responsible for the sex difference in CHD. This is apparent both when men and women of equal age are compared, and when age-related variations in the sex differences in plasma lipoproteins and CHD are considered. Differences between the sexes in lipoprotein concentrations are still present when sex differences in adiposity, cigarette smoking, physical activity, and diet are taken into account. Evidence relating these sex differences in CHD and lipoproteins to the effects of sex hormones is critically examined. It is commonly accepted that androgens induce changes in lipoprotein concentrations that would predispose towards CHD, whereas estrogens are held to have opposite effects. However, much of the evidence for this comes from studies of changes associated with administration of synthetic gonadal steroids or with changes in gonadal function. Studies of differences in lipoprotein metabolism in normal men and women are extremely limited. In males high-density lipoprotein (HDL) cholesterol levels fall at puberty, correlating with the rise in plasma testosterone concentrations. In females, HDL levels do not change at puberty, despite the rise in estrogen concentrations. Evidence for lipoprotein changes during the menopause, when estrogen levels decline, is equivocal. Similarly, the evidence for an increase in CHD incidence at the menopause is inconclusive. National mortality data indicate that the decreasing sex difference in CHD after 50 years of age is due to a declining rate of increase in men rather than to an acceleration in CHD incidence in women. In men

Impact of the 24-h ultramarathon race on homocysteine, oxidized low-density lipoprotein, and paraoxonase 1 levels in professional runners.

Science.gov (United States)

Benedetti, Serena; Catalani, Simona; Peda, Federica; Luchetti, Francesca; Citarella, Roberto; Battistelli, Serafina

2018-01-01

The impact of the 24-h ultramarathon race on homocysteine (Hcy) and oxidized low-density lipoprotein (oxLDL) levels, two well-recognized cardiovascular risk factors, has not been deeply investigated. Similarly, no information exists on paraoxonase 1 (PON1), an antioxidant enzyme associated with high-density lipoproteins, which may detoxify oxLDL and Hcy-thiolactone, hence preventing their proatherogenic action. Taking this into account, a competitive 24-h ultramarathon race was organized in Reggio-Emilia (Italy) recruiting professional runners (n = 14) from the Italian Ultramarathon and Trail Association. Blood samples were collected from each participant before, during (14 h), and immediately after (24 h) the competition, thus to monitor the serum changes in Hcy, oxLDL, and PON1 levels, as well as other oxidative stress-related parameters, namely reactive oxygen metabolites (ROM) and total antioxidant capacity (PAT). As a result, a significant PON1 increase was recorded after 14 h of racing that persisted until the end of the performance. The same trend was observed for PAT values, which positively correlated to PON1 levels (R = 0.643, P<0.001). Hcy, oxLDL, and ROM remained almost unchanged throughout the competition. In conclusion, the present study suggested a protective role of PON1 in sustaining the antioxidant defense system and contrasting lipoprotein oxidative modifications over the 24-h race, and did not specifically evidence either Hcy or oxLDL accumulation in such challenging sporting events.

Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus

DEFF Research Database (Denmark)

Drew, BG; Carey, AL; Natoli, AK

2011-01-01

We recently demonstrated that reconstituted high-density lipoprotein (rHDL) modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin. Given the key roles of both AMPK and insulin in fatty acid metabolism, the current study inve...

Correlation between serum lipoproteins and abdominal fat pad in ...

African Journals Online (AJOL)

GREGORY

2010-08-30

Aug 30, 2010 ... Triglyceride, cholesterol and VLDL concentrations were positively correlated with ... negative correlation was observed between high-density lipoprotein and ... Abbreviations: HDL, High density lipoprotein; VLDL, very low.

Measurement of rhesus monkey (Macaca mulatta) apolipoprotein B in serum by radioimmunoassay: comparison of immunoreactivities of rhesus and human low density lipoproteins

International Nuclear Information System (INIS)

Karlin, J.B.; Juhn, D.J.; Fless, G.; Scanu, A.M.; Rubenstein, A.H.

1978-01-01

A sensitive and specific double antibody radioimmunoassay for the major apolipoprotein (apoB) of rhesus (Macaca mulatta) serum very low density lipoprotein (VLDL) and low density lipoprotein (LDL) is described. The antiserum was raised to LDL (d 1.030 to 1.040 g/ml) and the LDL 2 (d 1.020 to 1.050 g/ml) was labeled with 125 I by the chloramine-T or iodine monochloride method. The assay, which was sensitive to 0.02 to 0.5 μg of LDL 2 , had an interassay coefficient of variation of 4.5%. This assay was successfully used to measure apoB in the whole serum and low density lipoproteins of control monkeys maintained on a standard Purina monkey chow (PMC) diet and of three groups of monkeys fed atherogenic diets: an average American diet, a 25% peanut oil and 2% cholesterol-supplemented PMC diet, and a 25% coconut oil and 2% cholesterol-supplemented PMC diet

Low-density lipoprotein apheresis: an evidence-based analysis.

Science.gov (United States)

2007-01-01

To assess the effectiveness and safety of low-density lipoprotein (LDL) apheresis performed with the heparin-induced extracorporeal LDL precipitation (HELP) system for the treatment of patients with refractory homozygous (HMZ) and heterozygous (HTZ) familial hypercholesterolemia (FH). BACKGROUND ON FAMILIAL HYPERCHOLESTEROLEMIA: Familial hypercholesterolemia is a genetic autosomal dominant disorder that is caused by several mutations in the LDL-receptor gene. The reduced number or absence of functional LDL receptors results in impaired hepatic clearance of circulating low-density lipoprotein cholesterol (LDL-C) particles, which results in extremely high levels of LDL-C in the bloodstream. Familial hypercholesterolemia is characterized by excess LDL-C deposits in tendons and arterial walls, early onset of atherosclerotic disease, and premature cardiac death. Familial hypercholesterolemia occurs in both HTZ and HMZ forms. Heterozygous FH is one of the most common monogenic metabolic disorders in the general population, occurring in approximately 1 in 500 individuals. Nevertheless, HTZ FH is largely undiagnosed and an accurate diagnosis occurs in only about 15% of affected patients in Canada. Thus, it is estimated that there are approximately 3,800 diagnosed and 21,680 undiagnosed cases of HTZ FH in Ontario. In HTZ FH patients, half of the LDL receptors do not work properly or are absent, resulting in plasma LDL-C levels 2- to 3-fold higher than normal (range 7-15mmol/L or 300-500mg/dL). Most HTZ FH patients are not diagnosed until middle age when either they or one of their siblings present with symptomatic coronary artery disease (CAD). Without lipid-lowering treatment, 50% of males die before the age of 50 and 25% of females die before the age of 60, from myocardial infarction or sudden death. In contrast to the HTZ form, HMZ FH is rare (occurring in 1 case per million persons) and more severe, with a 6- to 8-fold elevation in plasma LDL-C levels (range 15-25mmol

Reversal of hypercholesterolemia in apolipoprotein E2 and apolipoprotein E3-Leiden transgenic mice by adenovirus-mediated gene transfer of the VLDL receptor

NARCIS (Netherlands)

Dijk, K.W. van; Vlijmen, B.J.M. van; Zee, A. van der; Hof, B. van 't; Boom, H. van der; Kobayashi, K.; Chan, L.; Havekes, L.M.; Hofker, M.H.

1998-01-01

We have investigated the interaction of apolipoprotein E2(Arg158- Cys) (apoE2) and apolipoprotein E3Leiden (apoE3-Leiden) with the very low density lipoprotein (VLDL) receptor in vivo and in vitro to define the possible role of this receptor in lipoprotein metabolism and atherosclerosis. The in vivo

Evaluation of biodistribution and imaging of atherosclerotic lesions using 111In-labeled low-density lipoprotein

International Nuclear Information System (INIS)

Yamashina, Hisayo

1993-01-01

111 In-labeled low-density lipoprotein (LDL) was administered to Watanabe heritable hyperlipidemic rabbits (WHHL group) and control rabbits (control group) to evaluate its biodistribution and scintigraphic images by γ-camera and radioactivity of each organ. With external imaging, the heart, liver, kidney, bone and spleen of each rabbit were observed. By setting the region of interest, the liver/heart ratio of the WHHL group was significantly lower than that of the control group (p 111 In-labeled-LDL was recognized in the aortic arch, bifurcation of intercostal and celiac artery in the WHHL group. By the use of labeled LDL with the combination of γ-camera, it is capable of detecting the regulation of lipoprotein metabolism and imaging atherosclerotic lesions externally. (author)

Correlation between serum anyloid a low density lipoprotein and genotoxicity in smokers

International Nuclear Information System (INIS)

Jamil, A.; Rashid, A.; Majeed, A.; Naveed, A.K.

2018-01-01

Objective:To investigate the relation between serum amyloid A-low density lipoprotein (SAA-LDL) and genotoxicity in smokers. Study Design:An experimental study. Place and Duration of Study:Army Medical College, Rawalpindi and National Institute of Health (NIH), Islamabad, from June 2014 to February 2015. Methodology:Seventy healthy Sprague Dawley rats were purchased from NIH and exposed to cigarette smoke in smoke chamber for three months. Blood samples were drawn from each rat at the end of the study period. SAA-LDL was determined by enzyme-linked immunosorbent assay (ELISA). Genotoxicity was assessed by cytokinesis block micronucleus (CBMN) assay. Pearson correlation was used to find correlation between SAA-LDL and genotoxicity. Results:Strong positive correlation was found between SAA-LDL and micronuclei frequency in smoke-exposed rats (r=0.799, N=70, p <0.01). Conclusion:Statistically significant strong positive correlation between SAA-LDL and genotoxicity in smoke-exposed rats shows that changes in one is associated with changes in other and vice versa. (author)

The Role of High-Density Lipoproteins in Diabetes and Its Vascular Complications

Directory of Open Access Journals (Sweden)

Nathan K. P. Wong

2018-06-01

Full Text Available Almost 600 million people are predicted to have diabetes mellitus (DM by 2035. Diabetic patients suffer from increased rates of microvascular and macrovascular complications, associated with dyslipidaemia, impaired angiogenic responses to ischaemia, accelerated atherosclerosis, and inflammation. Despite recent treatment advances, many diabetic patients remain refractory to current approaches, highlighting the need for alternative agents. There is emerging evidence that high-density lipoproteins (HDL are able to rescue diabetes-related vascular complications through diverse mechanisms. Such protective functions of HDL, however, can be rendered dysfunctional within the pathological milieu of DM, triggering the development of vascular complications. HDL-modifying therapies remain controversial as many have had limited benefits on cardiovascular risk, although more recent trials are showing promise. This review will discuss the latest data from epidemiological, clinical, and pre-clinical studies demonstrating various roles for HDL in diabetes and its vascular complications that have the potential to facilitate its successful translation.

Lipoprotein receptors in copper-deficient rats: in vitro binding of high-density lipoprotein subfractions to liver membranes

International Nuclear Information System (INIS)

Hassel, C.A.

1986-01-01

Three studies were conducted to determine whether the elevated plasma and HDL cholesterol levels observed in copper-deficient rats could be explained by the interaction of 125 I-HDL subfractions with liver membrane preparations in vitro. Rats from all studies were randomly divided into two dietary treatments, copper-deficient and adequate (0.7 mg and 8.0 mg Cukg diet, respectively). Total binding data and computer derived estimates (K/sub d/ and B/sub max/) were used to compare differences between treatments. Binding data from all experiments conformed to a one-site model. In all cases, binding was saturable and EDTA and pronase insensitive. Treatment differences were observed in Study I ( 125 I-apo E-free HDL binding to crude liver membranes). Significantly lower total binding and B/sub max/ were observed when lipoproteins and membranes from copper-deficient animals were used in the assay. Competition experiments from Studies II and III demonstrate that the different HDL subfractions competed effectively with one another for binding sites, indicating that apo E is not a determinant in binding of rat 125 I-HDL subfractions to purified liver plasma membranes

Gemfibrozil treatment of the high triglyceride-low high-density lipoprotein cholesterol trait in men with established atherosclerosis

NARCIS (Netherlands)

Knipscheer, H. C.; Nurmohamed, M. T.; van den Ende, A.; Plaat, B.; Pruijs, H. J.; Mulder, W. J.; Kastelein, J. J.

1994-01-01

To study the short-term efficacy, tolerability and safety of the treatment with gemfibrozil 600 mg twice daily or placebo in male patients with established atherosclerosis, with a lipid profile matching the 'high triglyceride-low high-density lipoprotein (HDL) cholesterol trait'. Double-blind

Lipoprotein glomerulopathy treated with LDL-apheresis (Heparin-induced Extracorporeal Lipoprotein Precipitation system: a case report

Directory of Open Access Journals (Sweden)

Rivasi Paolo

2009-12-01

Full Text Available Abstract Introduction Lipoprotein glomerulopathy is a glomerulonephritis which was described for the first time by Saito in 1989 and is currently acknowledged as a separate nosological entity. It is histologically characterized by a marked dilatation of the glomerular capillaries and the presence of lipoprotein thrombi in the glomerular lumens. The dyslipidemic profile is similar to that of type III dyslipoproteinemia with Apolipoprotein E values that are often high; proteinuria and renal dysfunction are present. Proteinuria often does not respond to steroid and cytostatic treatments. The phenotypic expression of lipoprotein glomerulopathy is most probably correlated to a genetic alteration of the lipoprotein metabolism (mutation of the Apolipoprotein E coding gene. In literature, lipoprotein glomerulopathies have mainly been reported in Japanese and Chinese subjects, except for three cases in the Caucasian race, reported in France and the USA. Case presentation We describe the case of a 60-year-old female, Caucasian patient suffering from lipoprotein glomerulopathy, carrier of a new mutation on the Apolipoprotein E gene (Apolipoprotein EMODENA, and treated successfully with low density lipoprotein-apheresis with the Heparin induced extracorporeal lipoprotein precipitation system. After a first phase of therapeutic protocol with statins, the patient was admitted for nephrotic syndrome, renal failure and hypertension. Since conventional treatment alone was not able to control dyslipidemia, aphaeretic treatment with heparin-induced Extracorporeal Lipoprotein Precipitation - apheresis (HELP-apheresis was started to maintain angiotensin converting enzyme inhibitor therapy for the treatment of hypertension. Treatment with HELP-apheresis led to a complete remission of the proteinuria in a very short time (four months, as well as control of hypercholesterolemia and renal function recovery. Conclusion According to this case of lipoprotein glomerulopathy

Low-density Lipoprotein Improves Motility and Plasma Membrane Integrity of Cryopreserved Canine Epididymal Spermatozoa

OpenAIRE

N. Prapaiwan; T. Tharasanit; S. Punjachaipornpol; D. Yamtang; A. Roongsitthichai; W. Moonarmart; K. Kaeoket; S. Manee-in

2016-01-01

Cryopreservation of caudal epididymal spermatozoa is an effective technique to conserve genetic potentials of superior dogs when it is not possible to collect ejaculated spermatozoa. Although hen egg yolk is commonly supplemented into the semen extender, active substances within the egg yolk which protect sperm against cryoinjury remain to be discovered. Among its compositions, low-density lipoprotein (LDL) has been reported to have a cryoprotective property for sperm cryopreservation. Howeve...

A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans

DEFF Research Database (Denmark)

Vanhollebeke, Benoit; De Muylder, Géraldine; Nielsen, Marianne J

2008-01-01

The protozoan parasite Trypanosoma brucei is lysed by apolipoprotein L-I, a component of human high-density lipoprotein (HDL) particles that are also characterized by the presence of haptoglobin-related protein. We report that this process is mediated by a parasite glycoprotein receptor, which...... binds the haptoglobin-hemoglobin complex with high affinity for the uptake and incorporation of heme into intracellular hemoproteins. In mice, this receptor was required for optimal parasite growth and the resistance of parasites to the oxidative burst by host macrophages. In humans, the trypanosome...... immunity against the parasite....

Involvement of microtubules in lipoprotein degradation and utilization for steroidogenesis in cultured rat luteal cells

International Nuclear Information System (INIS)

Rajan, V.P.; Menon, K.M.

1985-01-01

Cells isolated from superovulated rat ovaries metabolize low density lipoprotein (LDL) and high density lipoprotein (HDL) of human or rat origin and use the lipoprotein-derived cholesterol as a precursor for progesterone production. Under in vitro conditions, both lipoproteins are internalized and degraded in the lysosomes, although degradation of HDL is of lower magnitude than that of LDL. In this report we have examined the role of cellular microtubules in the internalization and degradation of human LDL and HDL in cultured rat luteal cells. The microtubule depolymerizing agents colchicine, podophyllotoxin, vinblastine, and nocodazole as well as taxol, deuterium oxide, and dimethyl sulfoxide, which are known to rapidly polymerize cellular tubulin into microtubules, were used to block the function of microtubules. When these antimicrotubule agents were included in the incubations, degradation of the apolipoproteins of [ 125 I]iodo-LDL and [ 125 I]iodo-HDL by the luteal cells was inhibited by 50-85% compared to untreated control values. Maximum inhibitory effects were observed when the cells were preincubated with the inhibitor for at least 4 h at 37 C before treatment with the labeled lipoprotein. Lipoprotein-stimulated progesterone production by luteal cells was also inhibited by 50% or more in the presence of antimicrotubule agents. However, basal and hCG-stimulated progesterone production were unaffected by these inhibitors. The binding of [ 125 I]iodo-LDL and [ 125 I]iodo-HDL to luteal cell plasma membrane receptors was not affected by the microtubule inhibitors. Although binding was unaffected and degradation was impaired in the presence of the inhibitors, there was no detectable accumulation of undegraded lipoprotein within the cells during the 24 h of study

The Relationship between the Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Metabolic Syndrome.

Science.gov (United States)

Shin, Hyun-Gyu; Kim, Young-Kwang; Kim, Yong-Hwan; Jung, Yo-Han; Kang, Hee-Cheol

2017-11-01

Metabolic syndrome is associated with cardiovascular diseases and is characterized by insulin resistance. Recent studies suggest that the triglyceride/high-density lipoprotein cholesterol (TG/HDLC) ratio predicts insulin resistance better than individual lipid levels, including TG, total cholesterol, low-density lipoprotein cholesterol (LDLC), or HDLC. We aimed to elucidate the relationship between the TG/HDLC ratio and metabolic syndrome in the general Korean population. We evaluated the data of adults ≥20 years old who were enrolled in the Korean National Health and Nutrition Examination Survey in 2013 and 2014. Subjects with angina pectoris, myocardial infarction, stroke, or cancer were excluded. Metabolic syndrome was defined by the harmonized definition. We examined the odds ratios (ORs) of metabolic syndrome according to TG/HDLC ratio quartiles using logistic regression analysis (SAS ver. 9.4; SAS Institute Inc., Cary, NC, USA). Weighted complex sample analysis was also conducted. We found a significant association between the TG/HDLC ratio and metabolic syndrome. The cutoff value of the TG/HDLC ratio for the fourth quartile was ≥3.52. After adjustment, the OR for metabolic syndrome in the fourth quartile compared with that of the first quartile was 29.65 in men and 20.60 in women (Pmetabolic syndrome.

Macroporous poly(vinyl alcohol) microspheres bearing phosphate groups as a new adsorbent for low-density lipoprotein apheresis

Energy Technology Data Exchange (ETDEWEB)

Wang Weichao; Xie Hui; Ou Lailiang; Wang Lianyong; Yu Yaoting; Kong Deling [Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071 (China); Sun Lisha, E-mail: wly@nankai.edu.c, E-mail: kongdeling@nankai.edu.c [General Hospital, Tianjin Medical University, Tianjin 300052 (China)

2009-12-15

A new low-density lipoprotein (LDL) adsorbent with phosphate groups as the ligand was prepared in this study. Macroporous poly(vinyl acetate-co-triallyl isocyanurate) microspheres were prepared using a free-radical suspension polymerization method. A hydrolysis reaction in sodium hydroxide/methanol changed the materials into poly(vinyl alcohol) (PVA) microspheres. Further reaction with phosphorus oxychloride in anhydrous DMF led to the LDL adsorbent PVA-phosphate microspheres. The preparation conditions such as reaction time, temperature and the amount of phosphorus oxychloride were optimized. The adsorption of plasma lipoproteins was examined by in vitro adsorption assays. The influence of adsorption time, plasma volume and ionic strength on the adsorption capacity was investigated. The circulation adsorption showed that the pathogenic lipoproteins in the plasma such as total cholesterol (TC), LDL and triglyceride (TG) could be removed markedly, in which the removal percentages were 42.9%, 45.0% and 44.74%, respectively. However, the reduction of high-density lipoprotein (HDL) and other normal plasma components was very slight. For in vivo experiment, rabbits were fed with high-cholesterol food to develop a hyperlipidemia model and treated by extracorporeal blood perfusion using the PVA-phosphate columns. Eight hyperlipidemia rabbits were treated with the PVA-phosphate adsorbent, and the removal of TC, LDL and TG was 45.03 +- 6.64%, 48.97 +- 9.92% and 35.42 +- 14.17%, respectively. The sterilization and storage tests showed that the adsorbent was chemically and functionally stable. It could be easily sterilized by a common method and stored for months without loss of adsorption capacity. Therefore, this new PVA-phosphate-based LDL adsorbent may have potential for application in LDL apheresis.

Macroporous poly(vinyl alcohol) microspheres bearing phosphate groups as a new adsorbent for low-density lipoprotein apheresis

International Nuclear Information System (INIS)

Wang Weichao; Xie Hui; Ou Lailiang; Wang Lianyong; Yu Yaoting; Kong Deling; Sun Lisha

2009-01-01

A new low-density lipoprotein (LDL) adsorbent with phosphate groups as the ligand was prepared in this study. Macroporous poly(vinyl acetate-co-triallyl isocyanurate) microspheres were prepared using a free-radical suspension polymerization method. A hydrolysis reaction in sodium hydroxide/methanol changed the materials into poly(vinyl alcohol) (PVA) microspheres. Further reaction with phosphorus oxychloride in anhydrous DMF led to the LDL adsorbent PVA-phosphate microspheres. The preparation conditions such as reaction time, temperature and the amount of phosphorus oxychloride were optimized. The adsorption of plasma lipoproteins was examined by in vitro adsorption assays. The influence of adsorption time, plasma volume and ionic strength on the adsorption capacity was investigated. The circulation adsorption showed that the pathogenic lipoproteins in the plasma such as total cholesterol (TC), LDL and triglyceride (TG) could be removed markedly, in which the removal percentages were 42.9%, 45.0% and 44.74%, respectively. However, the reduction of high-density lipoprotein (HDL) and other normal plasma components was very slight. For in vivo experiment, rabbits were fed with high-cholesterol food to develop a hyperlipidemia model and treated by extracorporeal blood perfusion using the PVA-phosphate columns. Eight hyperlipidemia rabbits were treated with the PVA-phosphate adsorbent, and the removal of TC, LDL and TG was 45.03 ± 6.64%, 48.97 ± 9.92% and 35.42 ± 14.17%, respectively. The sterilization and storage tests showed that the adsorbent was chemically and functionally stable. It could be easily sterilized by a common method and stored for months without loss of adsorption capacity. Therefore, this new PVA-phosphate-based LDL adsorbent may have potential for application in LDL apheresis.

In vitro studies of PBT Nonwoven Fabrics adsorbent for the removal of low density lipoprotein from hyperlipemia plasma

Energy Technology Data Exchange (ETDEWEB)

Cao Ye; Wang Hong [Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052 (China); Yang Chao [State Key Lab of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 (China); Zhong Rui [Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052 (China); Lei Yu [Chengdu Blood Center, Chengdu 610041 (China); Sun Kang [State Key Lab of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 (China); Liu Jiaxin, E-mail: jxliu8122@vip.sina.com [Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052 (China)

2011-06-15

Polyanion ligands such as acrylic acid (AA) and heparin were grafted on PBT Nonwoven Fabrics (PBTNF) to study their effect on the adsorption of low density lipoprotein (LDL). These modified PBTNFs were characterized by Horizontal Attenuated Total Reflectance Fourier Transform Infrared spectroscopy and X-ray Photoelectron spectroscopy. The blood compatibilities of the modified PBTNFs were examined using in vitro hemolysis rate (HR), platelet adhesion, total protein (TP) and activated partial thromboplastin time. The results showed that direct immobilized heparin could improve PBTNF-PAA's blood compatibility and decrease the adsorption capability of useful high density lipoprotein, but would possess so low bioactivity that could not further improve the absorption of LDL and TC. Since the PBTNF-PAA55-Heparin adsorbent had quite good adsorption selectivity for these proteins, it can be an excellent candidate for depletion of LDL with good blood compatibility.

Density profile and cholesterol concentration of serum lipoproteins in experimental animals and human subjects on hypercholesterolaemic diets

NARCIS (Netherlands)

Beynen, A.C.; Terpstra, A.H.M.

1984-01-01

1. 1. The density profile of Sudan black stained serum lipoproteins was studied in human subjects and various animal species on diets supplemented with cholesterol. 2. 2. In the animals studied (rabbits, calves, mice, chickens, rats and guinea-pigs), the feeding of cholesterol resulted in an

Low-density lipoprotein electronegativity is a novel cardiometabolic risk factor.

Directory of Open Access Journals (Sweden)

Jing-Fang Hsu

Full Text Available BACKGROUND: Low-density lipoprotein (LDL plays a central role in cardiovascular disease (CVD development. In LDL chromatographically resolved according to charge, the most electronegative subfraction-L5-is the only subfraction that induces atherogenic responses in cultured vascular cells. Furthermore, increasing evidence has shown that plasma L5 levels are elevated in individuals with high cardiovascular risk. We hypothesized that LDL electronegativity is a novel index for predicting CVD. METHODS: In 30 asymptomatic individuals with metabolic syndrome (MetS and 27 healthy control subjects, we examined correlations between plasma L5 levels and the number of MetS criteria fulfilled, CVD risk factors, and CVD risk according to the Framingham risk score. RESULTS: L5 levels were significantly higher in MetS subjects than in control subjects (21.9±18.7 mg/dL vs. 11.2±10.7 mg/dL, P:0.01. The Jonckheere trend test revealed that the percent L5 of total LDL (L5% and L5 concentration increased with the number of MetS criteria (P<0.001. L5% correlated with classic CVD risk factors, including waist circumference, body mass index, waist-to-height ratio, smoking status, blood pressure, and levels of fasting plasma glucose, triglyceride, and high-density lipoprotein. Stepwise regression analysis revealed that fasting plasma glucose level and body mass index contributed to 28% of L5% variance. The L5 concentration was associated with CVD risk and contributed to 11% of 30-year general CVD risk variance when controlling the variance of waist circumference. CONCLUSION: Our findings show that LDL electronegativity was associated with multiple CVD risk factors and CVD risk, suggesting that the LDL electronegativity index may have the potential to be a novel index for predicting CVD. Large-scale clinical trials are warranted to test the reliability of this hypothesis and the clinical importance of the LDL electronegativity index.

Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis.

Science.gov (United States)

Hourcade-Potelleret, F; Laporte, S; Lehnert, V; Delmar, P; Benghozi, Renée; Torriani, U; Koch, R; Mismetti, P

2015-06-01

Epidemiological evidence that the risk of coronary heart disease is inversely associated with the level of high-density lipoprotein cholesterol (HDL-C) has motivated several phase III programmes with cholesteryl ester transfer protein (CETP) inhibitors. To assess alternative methods to predict clinical response of CETP inhibitors. Meta-regression analysis on raising HDL-C drugs (statins, fibrates, niacin) in randomised controlled trials. 51 trials in secondary prevention with a total of 167,311 patients for a follow-up >1 year where HDL-C was measured at baseline and during treatment. The meta-regression analysis showed no significant association between change in HDL-C (treatment vs comparator) and log risk ratio (RR) of clinical endpoint (non-fatal myocardial infarction or cardiac death). CETP inhibitors data are consistent with this finding (RR: 1.03; P5-P95: 0.99-1.21). A prespecified sensitivity analysis by drug class suggested that the strength of relationship might differ between pharmacological groups. A significant association for both statins (p<0.02, log RR=-0.169-0.0499*HDL-C change, R(2)=0.21) and niacin (p=0.02, log RR=1.07-0.185*HDL-C change, R(2)=0.61) but not fibrates (p=0.18, log RR=-0.367+0.077*HDL-C change, R(2)=0.40) was shown. However, the association was no longer detectable after adjustment for low-density lipoprotein cholesterol for statins or exclusion of open trials for niacin. Meta-regression suggested that CETP inhibitors might not influence coronary risk. The relation between change in HDL-C level and clinical endpoint may be drug dependent, which limits the use of HDL-C as a surrogate marker of coronary events. Other markers of HDL function may be more relevant. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Effect of bicarbonate on iron-mediated oxidation of low-density lipoprotein

Science.gov (United States)

Arai, Hirofumi; Berlett, Barbara S.; Chock, P. Boon; Stadtman, Earl R.

2005-07-01

Oxidation of low-density lipoprotein (LDL) may play an important role in atherosclerosis. We studied the effects of bicarbonate/CO2 and phosphate buffer systems on metal ion-catalyzed oxidation of LDL to malondialdehyde (MDA) and to protein carbonyl and MetO derivatives. Our results revealed that LDL oxidation in mixtures containing free iron or heme derivatives was much greater in bicarbonate/CO2 compared with phosphate buffer. However, when copper was substituted for iron in these mixtures, the rate of LDL oxidation in both buffers was similar. Iron-catalyzed oxidation of LDL was highly sensitive to inhibition by phosphate. Presence of 0.3-0.5 mM phosphate, characteristic of human serum, led to 30-40% inhibition of LDL oxidation in bicarbonate/CO2 buffer. Iron-catalyzed oxidation of LDL to MDA in phosphate buffer was inhibited by increasing concentrations of albumin (10-200 μM), whereas MDA formation in bicarbonate/CO2 buffer was stimulated by 10-50 μM albumin but inhibited by higher concentrations. However, albumin stimulated the oxidation of LDL proteins to carbonyl derivatives at all concentrations examined in both buffers. Conversion of LDL to MDA in bicarbonate/CO2 buffer was greatly stimulated by ADP, ATP, and EDTA but only when EDTA was added at a concentration equal to that of iron. At higher than stoichiometric concentrations, EDTA prevented oxidation of LDL. Results of these studies suggest that interactions between bicarbonate and iron or heme derivatives leads to complexes with redox potentials that favor the generation of reactive oxygen species and/or to the generation of highly reactive CO2 anion or bicarbonate radical that facilitates LDL oxidation. Freely available online through the PNAS open access option.Abbreviations: LDL, low-density lipoprotein; MDA, malondialdehyde; MetO, methionine sulfoxide.

Inhibition of triacylglycerol and apoprotein B secretion and of low density lipoprotein binding in Hep G2 cells by eicosapentaenoic acid

International Nuclear Information System (INIS)

Wong, S.H.; Nestel, P.J.

1987-01-01

The consumption of long chain polyunsaturated fatty acids of fish oils leads to profound lowering of plasma triacylglyercol (TAG) but not of plasma cholesterol. Reasons for this were investigated with the human hepatoma cell line, the Hep G2 cell. Incubations with oleic acid (OA), linoleic acid (LA) and the characteristic marine fatty acid eicosapentaenoic acid (EPA) enriched cellular TAG mass, though least with EPA. However, secretion of very low density lipoprotein (VLDL)-TAG and apoprotein B (apo B), measured from [ 3 H]-glycerol and [ 3 H]-leucine was markedly inhibited by EPA. Preincubation with LA reduced VLDL-TAG but not apo B secretion in comparison with OA which stimulated both. A possible effect on low density lipoprotein (LDL) removal was studied by measuring [ 125 I]-LDL binding. Preincubation with either EPA or LA inhibited the saturable binding of LDL, observed with OA and control incubations. The binding of lipoproteins containing chylomicron remnants was not affected by any of the fatty acids

Physical inactivity interacts with an endothelial lipase polymorphism to modulate high density lipoprotein cholesterol in the GOLDN study

Science.gov (United States)

BACKGROUND: Plasma high density lipoprotein (HDL) cholesterol (HDL-C) concentration is highly heritable but is also modifiable by environmental factors including physical activity. HDL-C response to exercise varies among individuals, and this variability may be associated with genetic polymorphism...

Correlation of structural stability with functional remodeling of high-density lipoproteins: the importance of being disordered.

Science.gov (United States)

Guha, Madhumita; Gao, Xuan; Jayaraman, Shobini; Gursky, Olga

2008-11-04

High-density lipoproteins (HDLs) are protein-lipid assemblies that remove excess cell cholesterol and prevent atherosclerosis. HDLs are stabilized by kinetic barriers that decelerate protein dissociation and lipoprotein fusion. We propose that similar barriers modulate metabolic remodeling of plasma HDLs; hence, changes in particle composition that destabilize HDLs and accelerate their denaturation may accelerate their metabolic remodeling. To test this notion, we correlate existing reports on HDL-mediated cell cholesterol efflux and esterification, which are obligatory early steps in cholesterol removal, with our kinetic studies of HDL stability. The results support our hypothesis and show that factors accelerating cholesterol efflux and esterification in model discoidal lipoproteins (including reduced protein size, reduced fatty acyl chain length, and/or increased level of cis unsaturation) destabilize lipoproteins and accelerate their fusion and apolipoprotein dissociation. Oxidation studies of plasma spherical HDLs show a similar trend: mild oxidation by Cu(2+) or OCl(-) accelerates cell cholesterol efflux, protein dissociation, and HDL fusion, while extensive oxidation inhibits these reactions. Consequently, moderate destabilization may be beneficial for HDL functions by facilitating insertion of cholesterol and lipophilic enzymes, promoting dissociation of lipid-poor apolipoproteins, which are primary acceptors of cell cholesterol, and thereby accelerating HDL metabolism. Therefore, HDL stability must be delicately balanced to maintain the structural integrity of the lipoprotein assembly and ensure structural specificity necessary for interactions of HDL with its metabolic partners, while facilitating rapid HDL remodeling and turnover at key junctures of cholesterol transport. The inverse correlation between HDL stability and remodeling illustrates the functional importance of structural disorder in macromolecular assemblies stabilized by kinetic barriers.

Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction

DEFF Research Database (Denmark)

Abdo, Adrian; Rayner, B.S.; van Reyk, D.M.

2017-01-01

Low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase (MPO) is present in atherosclerotic lesions, where it is implicated in the propagation of inflammation and acceleration of lesion development by multiple pathways, including the induction of endothelial......, although emerging evidence suggests that these particles have distinct biological properties. This is important because elevated plasma SCN- is linked with both the propagation and prevention of atherosclerosis. In this study, we demonstrate that both HOSCN- and HOCl-modified LDL inhibit endothelium......-mediated vasorelaxation ex vivo in rat aortic ring segments. In vitro experiments with human coronary artery endothelial cells show that HOSCN-modified LDL decreases in the production of nitric oxide (NO•) and induces the loss of endothelial nitric oxide synthase (eNOS) activity. This occurs to a similar extent...

Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease: cross-sectional, prospective, and case-control studies from the Copenhagen City Heart Study

DEFF Research Database (Denmark)

Wittrup, HH; Andersen, RV; Tybjærg-Hansen, A

2006-01-01

CONTEXT: Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). OBJECTIVE: The objective of this study was to investigate the influence of T(-93)G, G(-53)C, Asp9Asn, Gly188Glu, Asn291Ser, and Ser447Ter lipoprotein...... lipase genotypes on triglycerides, HDL, and IHD. DESIGN: The cross-sectional study involved 9004 adults. The prospective study consisted of 8817 adults developing 1001 IHD events over 23 yr. The case-control study involved 7818 non-IHD individuals vs. cohorts of 915 and 1062 IHD patients, respectively....... SETTING: The study was performed in the Danish general population (the Copenhagen City Heart Study). PARTICIPANTS: IHD was angina pectoris or myocardial infarction. MAIN OUTCOME MEASURES: Triglycerides, HDL, and IHD were the main outcome measures. RESULTS: Cross-sectionally, triglycerides varied...

A one-step separation of human serum high density lipoproteins 2 and 3 by rate-zonal density gradient ultracentrifugation in a swinging bucket rotor

NARCIS (Netherlands)

Groot, P.H.E.; Scheek, L.M.; Havekes, L.; Noort, W.L. van; Hooft, F.M. van 't

1982-01-01

A method was developed for the separation of the high density lipoprotein subclasses HDL2 and HDL3 from human serum. Six serum samples are fractionated in a single-step ultracentrifugal procedure using the Beckman (SW-40) swinging bucket rotor. The method is based on a difference in flotation rate

Increased cell motility and invasion upon knockdown of lipolysis stimulated lipoprotein receptor (LSR) in SW780 bladder cancer cells

DEFF Research Database (Denmark)

Herbsleb, Malene; Birkenkamp-Demtroder, Karin; Thykjaer, Thomas

2008-01-01

Mechanisms underlying the malignant development in bladder cancer are still not well understood. Lipolysis stimulated lipoprotein receptor (LSR) has previously been found to be upregulated by P53. Furthermore, we have previously found LSR to be differentially expressed in bladder cancer. Here we...... investigated the role of LSR in bladder cancer....

Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease

Directory of Open Access Journals (Sweden)

Toth PP

2016-05-01

atherogenic lipoproteins (including LDL, TRL, and TRL remnants, provides a better indication of CVD risk than LDL-C, particularly in patients with hypertriglyceridemia. This article aims to provide an overview of the available epidemiological, clinical, and genetic evidence relating to the atherogenicity of TRLs and their role in the progression of CVD. Keywords: triglycerides, non-highdensity, lipoprotein cholesterol, hypertriglyceridemia, lipoprotein lipase, chylomicrons, very low-density lipoproteins

Postprandial Hyperlipidemia and Remnant Lipoproteins.

Science.gov (United States)

Masuda, Daisaku; Yamashita, Shizuya

2017-02-01

Fasting hypertriglyceridemia is positively associated with the morbidity of coronary heart disease (CHD), and postprandial (non-fasting) hypertriglyceridemia is also correlated with the risk status for CHD, which is related to the increase in chylomicron (CM) remnant lipoproteins produced from the intestine. CM remnant particles, as well as oxidized low density lipoprotein (LDL) or very low density lipoprotein (VLDL) remnants, are highly atherogenic and act by enhancing systemic inflammation, platelet activation, coagulation, thrombus formation, and macrophage foam cell formation. The cholesterol levels of remnant lipoproteins significantly correlate with small, dense LDL; impaired glucose tolerance (IGT) and CHD prevalence. We have developed an assay of apolipoprotein (apo)B-48 levels to evaluate the accumulation of CM remnants. Fasting apoB-48 levels correlate with the morbidity of postprandial hypertriglyceridemia, obesity, type III hyperlipoproteinemia, the metabolic syndrome, hypothyroidism, chronic kidney disease, and IGT. Fasting apoB-48 levels also correlate with carotid intima-media thickening and CHD prevalence, and a high apoB-48 level is a significant predictor of CHD risk, independent of the fasting TG level. Diet interventions, such as dietary fibers, polyphenols, medium-chain fatty acids, diacylglycerol, and long-chain n-3 polyunsaturated fatty acids (PUFA), ameliorate postprandial hypertriglyceridemia, moreover, drugs for dyslipidemia (n-3 PUFA, statins, fibrates or ezetimibe) and diabetes concerning incretins (dipeptidyl-peptidase IV inhibitor or glucagon like peptide-1 analogue) may improve postprandial hypertriglyceridemia. Since the accumulation of CM remnants correlates to impaired lipid and glucose metabolism and atherosclerotic cardiovascular events, further studies are required to investigate the characteristics, physiological activities, and functions of CM remnants for the development of new interventions to reduce atherogenicity.

Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

Directory of Open Access Journals (Sweden)

Miloslava Hodúlová

Full Text Available The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8-13/strain and two progenitor strains SHR-Lx (n = 13 and BXH2/Cub (n = 18 were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG and cholesterol (C concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl. We have identified 14 loci (encompassing 1 to 65 genes on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b. Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant

Peri and Postparturient Concentrations of Lipid Lipoprotein Insulin and Glucose in Normal Dairy Cows

OpenAIRE

BAŞOĞLU, Abdullah; SEVİNÇ, Mutlu; OK, Mahmut

1998-01-01

In order to provide uniqe insight into the metabolic disturbences seen after calving cholesterol, triglycerid, high density lipoprotein, low density lipoprotein, very low density lipoprotein, glucose and insulin levels in serum were studied before calving (group I), in aerly (group II) and late (group III) lactation in 24 normal cows. Serum lipoproteins were separeted into various density classes by repeated ultracentrifugation. The results indicate that there was a rise in glucose, trygl...

Low fasting low high-density lipoprotein and postprandial lipemia

Directory of Open Access Journals (Sweden)

Sorodila Konstandina

2004-07-01

Full Text Available Abstract Background Low levels of high density lipoprotein (HDL cholesterol and disturbed postprandial lipemia are associated with coronary heart disease. In the present study, we evaluated the variation of triglyceride (TG postprandially in respect to serum HDL cholesterol levels. Results Fifty two Greek men were divided into 2 main groups: a the low HDL group (HDL p = 0.002. The low HDL group had significantly higher TG at 4, 6 and 8 h postprandially compared to the controls (p = 0.006, p = 0.002, and p p = 0.017 compared to the matched-control group. ROC analysis showed that fasting TG ≥ 121 mg/dl have 100% sensitivity and 81% specificity for an abnormal TG response (auc = 0.962, p Conclusions The delayed TG clearance postprandially seems to result in low HDL cholesterol even in subjects with low fasting TG. The fasting TG > 121 mg/dl are predictable for abnormal response to fatty meal.

Experimental atheromatous plaque imaging with 99mTc labelled low density lipoproteins in rabbit

International Nuclear Information System (INIS)

Wang Quanshi; Chen Yu; Wu Chunshan; Zhang Yijin; Liu Dexuan

1996-01-01

Atheromatous plaque imaging with 99m Tc labeled low density lipoproteins ( 99m Tc-LDL) were evaluated in rabbits for its clinical prospect. The 99m Tc-LDL atheromatous plaque imaging were performed in 9 rabbit models of atherosclerosis and 4 controls. The imagings were compared with autoradiographic and pathological results. The rabbit models of atherosclerosis by high cholesterol and high fat diet were successful in 100%. The atheromatous plaques well visualized in 8 of 9 rabbit models 24 hours after injection. The site and density of radioactive accumulation was closely correlated in autoradiography also. There was no radioactive spot in 4 controls. 99m Tc-LDL imaging may have a significant value for the diagnosis of atherosclerosis

Circulating Oxidized Low-Density Lipoprotein Levels Independently Predict 10-Year Progression of Subclinical Carotid Atherosclerosis: A Community-Based Cohort Study.

Science.gov (United States)

Gao, Shen; Zhao, Dong; Qi, Yue; Wang, Wei; Wang, Miao; Sun, Jiayi; Liu, Jun; Li, Yan; Liu, Jing

2018-03-07

To investigate the association between circulating oxidized low-density lipoprotein (ox-LDL) levels and progression of subclinical atherosclerosis and to examine whether this link is independent of other low-density lipoprotein (LDL)-related parameters. Totally, 804 subjects who were free of cardiovascular disease at baseline completed risk factor surveys and carotid ultrasound measurements in 2002 and 2012. Modified Poisson regression was performed to examine the association between baseline serum ox-LDL levels and the 10-year risk of progression of carotid atherosclerosis which was defined as the development of at least one new plaque in a previously plaque-free carotid segment at re-examination. The mean age of the subjects was 58.6±7.7 years at baseline and 43.3% were men. A total of 504 (62.7%) subjects had carotid plaque progression at re-examination. Subjects in the intermediate and highest tertiles of ox-LDL had a significantly higher adjusted risk of atherosclerosis progression than those in the lowest tertile [relative risk (95% confidence interval) 1.17 (1.01-1.34) for the intermediate tertile and 1.23 (1.07-1.42) for the highest tertile]. This association was independent of baseline levels of LDL-C, total LDL particle number, and small LDL particle number. This study demonstrates that serum ox-LDL levels predict 10-year progression of subclinical atherosclerosis. Moreover, this effect is independent of the cholesterol content, the number, and the size of LDL particles.

Localization of oxidized low-density lipoprotein and its relation to plaque morphology in human coronary artery.

Directory of Open Access Journals (Sweden)

Yasumi Uchida

Full Text Available OBJECTIVES: Oxidized low-density lipoprotein (oxLDL plays a key role in the formation of atherosclerotic plaques. However, its localization in human coronary arterial wall is not well understood. The present study was performed to visualize deposition sites and patterns of native oxLDL and their relation to plaque morphology in human coronary artery. METHODS: Evans blue dye (EB elicits a violet fluorescence by excitation at 345-nm and emission at 420-nm, and a reddish-brown fluorescence by excitation at 470-nm and emission at 515-nm characteristic of oxLDL only. Therefore, native oxLDL in excised human coronary artery were investigated by color fluorescent microscopy (CFM using EB as a biomarker. RESULTS: (1 By luminal surface scan with CFM, the % incidence of oxLDL in 38 normal segments, 41 white plaques and 32 yellow plaques that were classified by conventional angioscopy, was respectively 26, 44 and 94, indicating significantly (p<0.05 higher incidence in the latter than the former two groups. Distribution pattern was classified as patchy, diffuse and web-like. Web-like pattern was observed only in yellow plaques with necrotic core. (2 By transected surface scan, oxLDL deposited within superficial layer in normal segments and diffusely within both superficial and deep layers in white and yellow plaques. In yellow plaques with necrotic core, oxLDL deposited not only in the marginal zone of the necrotic core but also in the fibrous cap. CONCLUSION: Taken into consideration of the well-known process of coronary plaque growth, the results suggest that oxLDL begins to deposit in human coronary artery wall before plaque formation and increasingly deposits with plaque growth, exhibiting different deposition sites and patterns depending on morphological changes.

Ultracentrifugal and electrophoretic characteristics of the plasma lipoproteins of miniature schnauzer dogs with idiopathic hyperlipoproteinemia.

Science.gov (United States)

Whitney, M S; Boon, G D; Rebar, A H; Story, J A; Bottoms, G D

1993-01-01

To better characterize the idiopathic hyperlipoproteinemia of Miniature Schnauzer dogs, the plasma lipoproteins of 20 Miniature Schnauzers (MS) and 11 dogs of other breeds (DOB) were evaluated by ultracentrifugation, electrophoresis, and biochemical tests. Seventeen MS were healthy; 3 had diabetes mellitus. Plasma from 6 of 17 healthy and all 3 diabetic MS was visibly lipemic. Lipemia was slight to marked in healthy lipemic MS, and marked in diabetic ones. All DOB had clear plasma; 8 were healthy and 3 had diabetes. All healthy lipemic MS and diabetic lipemic MS had hypertriglyceridemia associated with excess very low density lipoproteins. Chylomicronemia was present in 4 of 6 healthy lipemic MS and all 3 diabetic lipemic MS. Lipoproteins with ultracentrifugal and electrophoretic characteristics of normal low density lipoprotein were lacking in 4 of 6 healthy lipemic MS. The lipoprotein patterns of 4 of 11 healthy nonlipemic MS were characterized by mild hypertriglyceridemia associated with increased very low density lipoproteins and a lack of lipoproteins with characteristics of normal low density lipoproteins. Lipoprotein patterns of diabetic DOB closely resembled those of healthy DOB; those of diabetic lipemic MS resembled those of markedly lipemic healthy lipemic MS. In conclusion, the hyperlipoproteinemia of Miniature Schnauzers is characterized by increased very low density lipoproteins with or without accompanying chylomicronemia; some affected dogs may have decreased low density lipoproteins.

Pyrene-Labeled Amphiphiles: Dynamic And Structural Probes Of Membranes And Lipoproteins

Science.gov (United States)

Pownall, Henry J.; Homan, Reynold; Massey, John B.

1987-01-01

Lipids and proteins are important functional and structural components of living organisms. Although proteins are frequently found as soluble components of plasma or the cell cytoplasm, many lipids are much less soluble and separate into complex assemblies that usually contain proteins. Cell membranes and plasma lipoproteins' are two important macro-molecular assemblies that contain both lipids and proteins. Cell membranes are composed of a variety of lipids and proteins that form an insoluble bilayer array that has relatively little curvature over distances of several nm. Plasma lipoproteins are different in that they are much smaller, water-soluble, and have highly curved surfaces. A model of a high density lipoprotein (HDL) is shown in Figure 1. This model (d - 10 nm) contains a surface of polar lipids and proteins that surrounds a small core of insoluble lipids, mostly triglycerides and cholesteryl esters. The low density (LDL) (d - 25 nm) and very low density (VLDL) (d 90 nm) lipoproteins have similar architectures, except the former has a cholesteryl ester core and the latter a core that is almost exclusively triglyceride (Figure 1). The surface proteins of HDL are amphiphilic and water soluble; the single protein of LDL is insoluble, whereas VLDL contains both soluble and insoluble proteins. The primary structures of all of these proteins are known.

The effect of interaction between Lipoprotein Lipase and ApoVLDL-II ...

African Journals Online (AJOL)

GREGO

2007-04-02

Apr 2, 2007 ... correlation between growth and fitness is not absolute, it ... significant differences are found in the plasma triglyceride ... (VLDL) and high density lipoprotein (HDL) concentration ... High-density lipoprotein cholesterol was.

Importance of high-density lipoprotein cholesterol levels in elderly diabetic individuals with type IIb dyslipidemia: A 2-year survey of cardiovascular events.

Science.gov (United States)

Ina, Koichiro; Hayashi, Toshio; Araki, Atsushi; Kawashima, Seinosuke; Sone, Hirohito; Watanabe, Hiroshi; Ohrui, Takashi; Yokote, Koutaro; Takemoto, Minoru; Kubota, Kiyoshi; Noda, Mitsuhiko; Noto, Hiroshi; Ding, Qun-Fang; Zhang, Jie; Yu, Ze-Yun; Yoon, Byung-Koo; Nomura, Hideki; Kuzuya, Masafumi

2014-10-01

The risk factors for ischemic heart disease (IHD) or cerebrovascular accident (CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia. The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.4 ± 9.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia. The 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged 75 years (n=168, 190 and 104, respectively). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol/HDL-C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged dyslipidemia who were aged dyslipidemia who were aged <75 years. © 2013 Japan Geriatrics Society.

Serum and urinary lipoproteins in the human nephrotic syndrome: evidence for renal catabolism of lipoproteins

Energy Technology Data Exchange (ETDEWEB)

Shore, V.G.; Forte, T.; Licht, H.; Lewis, S.B.

1982-03-01

The urinary excretion of lipoproteins and the possibility of catabolic alterations on glomerular filtration were investigated in four nephrotic subjects difering in etiology, serum lipoprotein profile, and 24 hr urinary output of protein and lipids. The apolipoproteins and lipoproteins of urine were compared with those of serum with respect to distribution profile, physical properties, and composition. As expected from molecular sieving effects during glomerular filtration, the urinary HDL were more abundant than the lower density lipoproteins even when the plasma LDL was elevated markedly. Intact apolipoproteins were not found in the concentrated urinary fraction isolated by ultrafiltration between the limits of 10/sup 4/ and 5 x 10/sup 4/ daltons. On the basis of immunoreactivity, gel electrophoresis, and amino acid composition, apolipoproteins B and AI are the major and minor proteins, respectively, of urinary LDL, and apo B is the major protein of the urinary IDL and VLDL. Apolipoproteins AI, AII, CI, CIII, and possibly AIV were isolated from the urinary HDL. As much as 20% of the protein moiety of the urinary HDL appeared to be large apolipoprotien fragments with molecular weights and isoelectric points similar to those of apo CII and apo CIII. The lower density classes of urinary lipoproteins also appeared to have lost apo E and apo C's and to have undergone partial proteolysis.

RRR- and SRR-alpha-tocopherols are secreted without discrimination in human chylomicrons, but RRR-alpha-tocopherol is preferentially secreted in very low density lipoproteins

International Nuclear Information System (INIS)

Traber, M.G.; Burton, G.W.; Ingold, K.U.; Kayden, H.J.

1990-01-01

Five subjects ingested in a single oral dose containing 50 mg each of 2R,4'R,8'R-alpha-(5,7-(C2H3)2)tocopheryl acetate (d6-RRR-alpha-tocopheryl acetate) with natural stereochemistry, and of 2S,4'R,8'R-alpha-(5-C2H3)tocopheryl acetate (d3-SRR-alpha-tocopheryl acetate). These are two of eight stereoisomers in synthetic vitamin E. By day 1 the plasma and red blood cells were enriched fourfold with d6-RRR-alpha-tocopherol (P less than 0.004). The ratio of d6-RRR-/d2-SRR- further increased over the succeeding 4 days, because the d3-SRR- decreased at a faster rate than did the d6-RRR-stereoisomer. Plasma and lipoproteins were isolated at intervals during the first day, and daily for 3 days, from four additional subjects fed a mixture of equal amounts of the deuterated tocopherols. The plasma contained similar concentrations of the two forms until 11 h, when the d6-RRR-alpha-tocopherol concentration became significantly greater (P less than 0.05). The chylomicrons contained similar concentrations of the two deuterated tocopherols, but the VLDL (very low density lipoproteins) became preferentially enriched in d6-RRR-alpha-tocopherol by 11 h. The pattern of the deuterated tocopherols shows that during chylomicron catabolism all of the plasma lipoproteins were labeled equally with both tocopherols, but that during the subsequent VLDL catabolism the low and high density lipoproteins became enriched in d6-RRR-alpha-tocopherol. These results suggest the existence of a mechanism in the liver for assembling VLDL preferentially enriched in RRR- relative to SRR-alpha-tocopherol

The Correlation between the Triglyceride to High Density Lipoprotein Cholesterol Ratio and Computed Tomography-Measured Visceral Fat and Cardiovascular Disease Risk Factors in Local Adult Male Subjects

OpenAIRE

Park, Hye-Rin; Shin, Sae-Ron; Han, A Lum; Jeong, Yong Joon

2015-01-01

Background We studied the association between the triglyceride to high-density lipoprotein cholesterol ratio and computed tomography-measured visceral fat as well as cardiovascular risk factors among Korean male adults. Methods We measured triglycerides, high density lipoprotein cholesterol, body mass, waist circumference, fasting plasma glucose, hemoglobin A1c, systolic blood pressure, diastolic blood pressure, visceral fat, and subcutaneous fat among 372 Korean men. The visceral fat and sub...

Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans

NARCIS (Netherlands)

Brunham, Liam R.; Tietjen, Ian; Bochem, Andrea E.; Singaraja, Roshni R.; Franchini, Patrick L.; Radomski, Chris; Mattice, Maryanne; Legendre, Annick; Hovingh, G. Kees; Kastelein, John J. P.; Hayden, Michael R.

2011-01-01

The scavenger receptor class B, member 1 (SR-BI), is a key cellular receptor for high-density lipoprotein (HDL) in mice, but its relevance to human physiology has not been well established. Recently a family was reported with a mutation in the gene encoding SR-BI and high HDL cholesterol (HDL-C).

Sortilins: new players in lipoprotein metabolism

DEFF Research Database (Denmark)

Willnow, Thomas; Kjølby, Mads Fuglsang; Nykjær, Anders

2011-01-01

PURPOSE OF REVIEW: Sortilins are sorting receptors that direct proteins through secretory and endocytic pathways of the cell. Previously, these receptors have been shown to play important roles in regulating protein transport in neurons and to control neuronal viability and death in many diseases...... on the importance of sorting receptors in control of cellular and systemic lipoprotein metabolism and how altered trafficking pathways may represent a major risk factor for dyslipidemia and atherosclerosis in the human population....

Insulin-like growth factor-II receptors in cultured rat hepatocytes: regulation by cell density

International Nuclear Information System (INIS)

Scott, C.D.; Baxter, R.C.

1987-01-01

Insulin-like growth factor-II (IGF-II) receptors in primary cultures of adult rat hepatocytes were characterized and their regulation by cell density examined. In hepatocytes cultured at 5 X 10(5) cells per 3.8 cm2 plate [ 125 I]IGF-II bound to specific, high affinity receptors (Ka = 4.4 +/- 0.5 X 10(9) l/mol). Less than 1% cross-reactivity by IGF-I and no cross-reactivity by insulin were observed. IGF-II binding increased when cells were permeabilized with 0.01% digitonin, suggesting the presence of an intracellular receptor pool. Determined by Scatchard analysis and by polyacrylamide gel electrophoresis after affinity labeling, the higher binding was due solely to an increase in binding sites present on 220 kDa type II IGF receptors. In hepatocytes cultured at low densities, the number of cell surface receptors increased markedly, from 10-20,000 receptors per cell at a culture density of 6 X 10(5) cells/well to 70-80,000 receptors per cell at 0.38 X 10(5) cells/well. The increase was not due simply to the exposure of receptors from the intracellular pool, as a density-related increase in receptors was also seen in cells permeabilized with digitonin. There was no evidence that IGF binding proteins, either secreted by hepatocytes or present in fetal calf serum, had any effect on the measurement of receptor concentration or affinity. We conclude that rat hepatocytes in primary culture contain specific IGF-II receptors and that both cell surface and intracellular receptors are regulated by cell density

Genetic Variant of the Scavenger Receptor BI in Humans

NARCIS (Netherlands)

Vergeer, Menno; Korporaal, Suzanne J. A.; Franssen, Remco; Meurs, Illiana; Out, Ruud; Hovingh, G. Kees; Hoekstra, Menno; Sierts, Jeroen A.; Dallinga-Thie, Geesje M.; Motazacker, Mohammad Mahdi; Holleboom, Adriaan G.; van Berkel, Theo J. C.; Kastelein, John J. P.; van Eck, Miranda; Kuivenhoven, Jan Albert

2011-01-01

BACKGROUND In mice, the scavenger receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice. It

Genetic variant of the scavenger receptor BI in humans

NARCIS (Netherlands)

Vergeer, Menno; Korporaal, Suzanne J A; Franssen, Remco; Meurs, Illiana; Out, Ruud; Hovingh, G Kees; Hoekstra, Menno; Sierts, Jeroen A; Dallinga-Thie, Geesje M; Motazacker, Mohammad Mahdi; Holleboom, Adriaan G; Van Berkel, Theo J C; Kastelein, John J P; Van Eck, Miranda; Kuivenhoven, Jan Albert

2011-01-01

BACKGROUND: In mice, the scavenger receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice.

The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques

NARCIS (Netherlands)

Barazza, Alessandra; Blachford, Courtney; Even-Or, Orli; Joaquin, Victor A.; Briley-Saebo, Karen C.; Chen, Wei; Jiang, Xian-Cheng; Mulder, Willem J. M.; Cormode, David P.; Fayad, Zahi A.; Fisher, Edward A.

2013-01-01

We have previously reported enhancing the imaging of atherosclerotic plaques in mice using reconstituted high density lipoproteins (HDL) as nanocarriers for the MRI contrast agent gadolinium (Gd). This study focuses on the underlying mechanisms of Gd delivery to atherosclerotic plaques. HDL, LDL,

Characterization of blood lipoproteins and validation of cholesterol and triacylglycerol assays for free-ranging polar bears (Ursus maritimus).