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Matti Jauhiainen - One of the best experts on this subject based on the ideXlab platform.
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influence of isoforms and carboxyl terminal truncations on the capacity of apolipoprotein e to associate with and activate Phospholipid Transfer protein
Biochemistry, 2015Co-Authors: Ioannis Dafnis, Matti Jauhiainen, J Metso, Vassilis I Zannis, Angeliki ChroniAbstract:Phospholipid Transfer protein (PLTP), a main protein in lipid and lipoprotein metabolism, exists in high-activity (HA-PLTP) and low-activity (LA-PLTP) forms in human plasma. Proper Phospholipid Transfer activity of PLTP is modulated by interactions with various apolipoproteins (apo) including apoE. The domains of apoE involved in interactions with PLTP are not known. Here we analyzed the capacity of recombinant apoE isoforms and apoE4 mutants with progressive carboxyl-terminal deletions to bind to and activate HA-PLTP and LA-PLTP. Our analyses demonstrated that lipid-free apoE isoforms bind to both HA-PLTP and LA-PLTP, resulting in Phospholipid Transfer activation, with apoE3 inducing the highest PLTP activation. The isoform-specific differences in apoE/PLTP binding and PLTP activation were abolished following apoE lipidation. Lipid-free apoE4[Δ(260-299)], apoE4[Δ(230-299)], apoE4[Δ(203-299)], and apoE4[Δ(186-299)] activated HA-PLTP by 120-160% compared to full-length apoE4. Lipid-free apoE4[Δ(186-299)] also activated LA-PLTP by 85% compared to full-length apoE4. All lipidated truncated apoE4 forms displayed a similar effect on HA-PLTP and LA-PLTP activity as full-length apoE4. Strikingly, lipid-free or lipidated full-length apoE4 and apoE4[Δ(186-299)] demonstrated similar binding capacity to LA-PLTP and HA-PLTP. Biophysical studies showed that the carboxyl-terminal truncations of apoE4 resulted in small changes of the structural or thermodynamic properties of lipidated apoE4, that were much less pronounced compared to changes observed previously for lipid-free apoE4. Overall, our findings show an isoform-dependent binding to and activation of PLTP by lipid-free apoE. Furthermore, the domain of apoE4 required for PLTP activation resides within its amino-terminal 1-185 region. The apoE/PLTP interactions can be modulated by the conformation and lipidation state of apoE.
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dry eye symptoms are increased in mice deficient in Phospholipid Transfer protein pltp
American Journal of Pathology, 2011Co-Authors: Niko Setala, Jari Metso, Matti Jauhiainen, Antti Sajantila, Juha M. HolopainenAbstract:In the tear fluid the outermost part facing the tear–air interface is composed of lipids preventing evaporation of the tears. Phospholipid Transfer protein (PLTP) mediates Phospholipid Transfer processes between serum lipoproteins and is also a normal component of human tears. To study whether PLTP plays any functional role in tear fluid we investigated PLTP-deficient mice, applying functional and morphologic analyses under normal housing and experimentally induced dry eye conditions. Aqueous tear fluid production, corneal epithelial morphology, barrier function, and occludin expression were assessed. In mice with a full deficiency of functional PLTP enhanced corneal epithelial damage, increased corneal permeability to carboxyfluorescein, and decreased corneal epithelial occludin expression were shown. These pathologic signs were worsened by experimentally induced dry eye both in wild-type and PLTP knock-out mice. Deficiency in the production of tear PLTP in mice is accompanied by corneal epithelial damage, a feature that is typical in human dry eye syndrome (DES). To complement animal experiments we collected tear fluid from human dry eye patients as well as healthy control subjects. Increased tear fluid PLTP activity was observed among DES patients. In conclusion, the presence of PLTP in tear fluid appears to be essential for maintaining a healthy and functional ocular surface. Increased PLTP activity in human tear fluid in DES patients suggests an ocular surface protective role for this lipid Transfer protein.
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Interaction of Phospholipid Transfer protein with human tear fluid mucins
Journal of lipid research, 2010Co-Authors: Niko L. Setälä, Jari Metso, Ove Eriksson, Juha M. Holopainen, Gebrenegus Yohannes, Jaakko Hiidenhovi, Leif C. Andersson, Alexandra Robciuc, Matti JauhiainenAbstract:In addition to circulation, where it Transfers Phospholipids between lipoprotein particles, Phospholipid Transfer protein (PLTP) was also identified as a component of normal tear fluid. The purpose of this study was to clarify the secretion route of tear fluid PLTP and elucidate possible interactions between PLTP and other tear fluid proteins. Human lacrimal gland samples were stained with monoclonal antibodies against PLTP. Heparin-Sepharose (H-S) affinity chromatography was used for specific PLTP binding, and coeluted proteins were identified with MALDI-TOF mass spectrometry or Western blot analysis. Immunoprecipitation assay and blotting with specific antibodies helped to identify and characterize PLTP-mucin interaction in tear fluid. Human tear fluid PLTP is secreted from the lacrimal gland. MALDI-TOF analysis of H-S fractions identified several candidate proteins, but protein-protein interaction assays revealed only ocular mucins as PLTP interaction partners. We suggest a dual role for PLTP in human tear fluid: (1) to scavenge lipophilic substances from ocular mucins and (2) to maintain the stability of the anterior tear lipid film. PLTP may also play a role in the development of ocular surface disease.
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avian Phospholipid Transfer protein causes hdl conversion without affecting cholesterol efflux from macrophages
WOS, 2009Co-Authors: Jani Saarela, Jari Metso, Wolfgang J Schneider, Matti JauhiainenAbstract:Abstract Circulatory Phospholipid Transfer protein (PLTP) has two major functions: 1) Transfer of Phospholipids towards HDL particles; and 2) modulation of HDL size and composition via the HDL conversion process. In the laying hen (Gallus gallus), the massive oocyte-targeted lipid flow is achieved through the concerted actions of lipases, lipid Transfer proteins, and relatives of the LDL receptor family. The aim of the study was to gain insights into the structure and functions of chicken PLTP. The results demonstrate that PLTP is highly conserved from chicken to mammals, as (i) chicken PLTP is associated with plasma HDL; (ii) it clearly possesses Phospholipid Transfer activity; (iii) it is inactivated at + 58 °C; and (iv) it mediates conversion of avian and human HDL into small preβ-mobile HDL and large fused α-mobile HDL particles. Our data show that HDL from different chicken models is similar in chemical and physical properties to that of man based on PLTP activity, cholesterol efflux, and HDL conversion assays. In contrast to mammals, PLTP-facilitated HDL remodeling did not enhance cholesterol efflux efficiency of chicken HDL particles.
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low Phospholipid Transfer protein pltp is a risk factor for peripheral atherosclerosis
Atherosclerosis, 2008Co-Authors: Wilfried Schgoer, Matti Jauhiainen, Roland Gander, Philipp Eller, Andreas Ritsch, Thomas Mueller, Andreas Wehinger, Ivan Tancevski, Karin Salzmann, Meinhard HaltmayerAbstract:Abstract Objective Phospholipid Transfer protein (PLTP) facilitates cholesterol efflux from cells, intravascular HDL remodelling and Transfer of vitamin E and endotoxin. In humans, the relationship of PLTP to atherosclerosis is unknown. However, strong coronary risk factors like obesity, diabetes, cigarette smoking and inflammation increase circulating levels of active PLTP. The aim of the present, cross-sectional study was to analyze the relationship of PLTP to peripheral arterial disease, a marker of generalized atherosclerosis, independently of potentially confounding factors like obesity, diabetes and smoking. Methods We performed a case control study in 153 patients with symptomatic peripheral arterial disease (PAD) and 208 controls free of vascular disease. Smokers and patients with diabetes mellitus were excluded. A lipoprotein-independent assay was used for measurement of circulating bioactive PLTP and an ELISA utilizing a monoclonal antibody was used to analyze PLTP mass. Results PLTP activity was significantly decreased in patients with PAD 5.5 (4.6–6.4)(median (25th–75th percentile)) versus 5.9 (5.1–6.9) μmol/mL/h in controls ( p = 0.001). In contrast, PLTP mass was similar in patients with PAD 8.5 μg/mL (7.3–9.5) and in controls 8.3 μg/mL (6.9–9.7) ( p = 0.665). Multivariate logistic regression analysis revealed that PLTP activity is independently associated with the presence of PAD. PLTP activity was similar in patients with and without lipid-lowering drugs ( p = 0.396). Conclusion Our results show that in non-diabetic, non-smoking subjects low rather than high PLTP activity is a marker for the presence of peripheral arterial disease and that distribution of PLTP between high-activity and low-activity forms may be compromised in atherosclerosis.
Xiancheng Jiang - One of the best experts on this subject based on the ideXlab platform.
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Phospholipid Transfer protein and alpha 1 antitrypsin regulate hck kinase activity during neutrophil degranulation
Scientific Reports, 2018Co-Authors: Pius Ochieng, Xiancheng Jiang, Sridesh Nath, Reane Macarulay, Edward Eden, Abdoulaye J Dabo, Michael Campos, Robert F Foronjy, Patrick GeraghtyAbstract:Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that Phospholipid Transfer protein (PLTP) prevents neutrophil degranulation but serine proteases, which AAT inhibits, cleave PLTP in diseased airways. We propose to identify if airway PLTP activity can be restored by AAT augmentation therapy and how PLTP subdues degranulation of neutrophils in AAT deficient subjects. Airway PLTP activity was lower in AAT deficient patients but elevated in the airways of patients on augmentation therapy. Functional AAT protein (from PiMM homozygotes) prevented PLTP cleavage unlike its mutated ZZ variant (PiZZ). PLTP lowered leukotriene B4 induced degranulation of primary, secondary and tertiary granules from neutrophils from both groups (n = 14/group). Neutrophils isolated from Pltp knockout mice have enhance neutrophil degranulation. Both AAT and PLTP reduced neutrophil degranulation and superoxide production, possibly though their inhibition of the Src tyrosine kinase, Hck. Src kinase inhibitors saracatinib and dasatinib reduced neutrophil degranulation and superoxide production. Therefore, AAT protects PLTP from proteolytic cleavage and both AAT and PLTP mediate degranulation, possibly via Hck tyrosine kinase inhibition. Deficiency of AAT could contribute to reduced lung PLTP activity and elevated neutrophil signaling associated with lung disease.
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prodomain of furin promotes Phospholipid Transfer protein proteasomal degradation in hepatocytes
Journal of the American Heart Association, 2018Co-Authors: Xia Lei, Shucun Qin, Weijun Jin, Hui Jiang, John W M Creemers, Ming Zhang, Xiancheng JiangAbstract:Background Phospholipid Transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development; however, little is known about the regulation of PLTP. The effect of hepatic prodomain of furin (profurin) expression on PLTP processing and function is investigated. Methods and Results We used adenovirus expressing profurin in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We coexpressed PLTP and profurin in human hepatoma cell line cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity, and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explored the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP; instead, it forms a complex with PLTP, likely through its prodomain. Conclusions Our study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin expression, which could be a novel posttranslational mechanism underlying PLTP regulation.
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Phospholipid Transfer protein its impact on lipoprotein homeostasis and atherosclerosis
Journal of Lipid Research, 2018Co-Authors: Xiancheng JiangAbstract:Phospholipid Transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development in humans; however, we still do not quite understand the mechanisms. In mouse models, PLTP overexpression induces atherosclerosis, while its deficiency reduces it. Thus, mouse models were used to explore the mechanisms. In this review, I summarize the major progress made in the PLTP research field and emphasize its impact on lipoprotein metabolism and atherosclerosis, as well as its regulation.
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REVIEW The impact of Phospholipid Transfer protein (PLTP) on lipoprotein metabolism
2014Co-Authors: Xiancheng Jiang, Weijun Jin, Mahmood M HussainAbstract:It has been reported that Phospholipid Transfer protein (PLTP) is an independent risk factor for human coronary artery disease. In mouse models, it has been demonstrated that PLTP overexpression induces atherosclerosis, while its deficiency reduces it. PLTP is considered a promising target for pharmacological intervention to treat atherosclerosis. However, we must still answer a number of questions before its pharmaceutical potential can be fully explored. In this review, we summarized the recent progresses made in the PLTP research field and focused on its effect on apoB-containing- triglyceride-rich particle and HDL metabolism. Phospholipid Transfer protein (PLTP) PLTP belongs to a family of lipid Transfer/lipopolysaccharidebinding proteins, including cholesterol ester Transfer protein (CETP), lipopolysaccharide-binding protein (LBP) and bactericidal/permeability increasing protein (BPI) [1]. It is a monomeric protein of 81 kDa [2]. Besides Phospholipids, PLTP efficiently Transfers diacylglycerol, α-tocopherol, cerebroside, and lipopolysaccharides [3]. Therefore, plasma PLT
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cathepsin g degradation of Phospholipid Transfer protein pltp augments pulmonary inflammation
The FASEB Journal, 2014Co-Authors: Anthony Brehm, Xiancheng Jiang, Edward Eden, Abdoulaye J Dabo, Michael Campos, Patrick Geraghty, Itsaso Garciaarcos, Adam Gaffney, Jeanine Darmiento, Robert F ForonjyAbstract:Phospholipid Transfer protein (PLTP) regulates Phospholipid transport in the circulation and is highly expressed within the lung epithelium, where it is secreted into the alveolar space. Since PLTP expression is increased in chronic obstructive pulmonary disease (COPD), this study aimed to determine how PLTP affects lung signaling and inflammation. Despite its increased expression, PLTP activity decreased by 80% in COPD bronchoalveolar lavage fluid (BALF) due to serine protease cleavage, primarily by cathepsin G. Likewise, PLTP BALF activity levels decreased by 20 and 40% in smoke-exposed mice and in the media of smoke-treated small airway epithelial (SAE) cells, respectively. To assess how PLTP affected inflammatory responses in a lung injury model, PLTP siRNA or recombinant protein was administered to the lungs of mice prior to LPS challenge. Silencing PLTP at baseline caused a 68% increase in inflammatory cell infiltration, a 120 and 340% increase in ERK and NF-κB activation, and increased MMP-9, IL1β, and IFN-γ levels after LPS treatment by 39, 140, and 190%, respectively. Conversely, PLTP protein administration countered these effects in this model. Thus, these findings establish a novel anti-inflammatory function of PLTP in the lung and suggest that proteolytic cleavage of PLTP by cathepsin G may enhance the injurious inflammatory responses that occur in COPD.—Brehm, A., Geraghty, P., Campos, M., Garcia-Arcos, I., Dabo, A. J., Gaffney, A., Eden, E., Jiang, X.-C., D'Armiento, J., Foronjy, R. Cathepsin G degradation of Phospholipid Transfer protein (PLTP) augments pulmonary inflammation.
Christian Ehnholm - One of the best experts on this subject based on the ideXlab platform.
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macrophage Phospholipid Transfer protein contributes significantly to total plasma Phospholipid Transfer activity and its deficiency leads to diminished atherosclerotic lesion development
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: R. Vikstedt, Jari Metso, Christian Ehnholm, Matti Jauhiainen, Reeni B. Hildebrand, Theo J.c. Van Berkel, Miranda Van EckAbstract:Objective— Systemic Phospholipid Transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic lesion development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% ( P <0.01 for difference in lesion area) reduction in aortic root lesion area as compared with mice possessing functional macrophage PLTP (384±36*103 μm2 in the PLTP−M/−M group (n=10), as compared with 539±35*103 μm2 in the PLTP+M/+M group (n=14)) after 9 weeks of Western-type diet feeding. The decreased lesion size in the PLTP−M/−M group coincided with significantly lower serum total cholesterol, free cholesterol, and triglyceride levels in these mice. Furthermore, plasma PLTP activity in the PLTP−M/−M group was 2-fold ( P <0.001) lower than that in the PLTP+M/+M group. Conclusion— Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic lesion development in low-density lipoprotein receptor knockout mice on Western-type diet.
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absence of endogenous Phospholipid Transfer protein impairs abca1 dependent efflux of cholesterol from macrophage foam cells
Journal of Lipid Research, 2006Co-Authors: Miriam Leerueckert, R. Vikstedt, Jari Metso, Christian Ehnholm, Petri T Kovanen, Matti JauhiainenAbstract:In vitro experiments have demonstrated that exogenous Phospholipid Transfer protein (PLTP), i.e. purified PLTP added to macrophage cultures, influences ABCA1-mediated cholesterol efflux from macrophages to HDL. To investigate whether PLTP produced by the macrophages (i.e., endogenous PLTP) is also part of this process, we used peritoneal macrophages derived from PLTP-knockout (KO) and wild-type (WT) mice. The macrophages were transformed to foam cells by cholesterol loading, and this resulted in the upregulation of ABCA1. Such macrophage foam cells from PLTP-KO mice released less cholesterol to lipid-free apolipoprotein A-I (apoA-I) and to HDL than did the corresponding WT foam cells. Also, when plasma from either WT or PLTP-KO mice was used as an acceptor, cholesterol efflux from PLTP-KO foam cells was less efficient than that from WT foam cells. After cAMP treatment, which upregulated the expression of ABCA1, cholesterol efflux from PLTP-KO foam cells to apoA-I increased markedly and reached a level similar to that observed in cAMP-treated WT foam cells, restoring the decreased cholesterol efflux associated with PLTP deficiency. These results indicate that endogenous PLTP produced by macrophages contributes to the optimal function of the ABCA1-mediated cholesterol efflux-promoting machinery in these cells. Whether macrophage PLTP acts at the plasma membrane or intracellularly or shuttles between these compartments needs further study.
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Phospholipid Transfer Protein Is Present in Human Tear Fluid
Biochemistry, 2005Co-Authors: Matti Jauhiainen, Jari Metso, Christian Ehnholm, Timo Tervo, Niko L. Setälä, Ove Eriksson, Juha M. HolopainenAbstract:The human tear fluid film consists of a superficial lipid layer, an aqueous middle layer, and a hydrated mucin layer located next to the corneal epithelium. The superficial lipid layer protects the eye from drying and is composed of polar and neutral lipids provided by the meibomian glands. Excess accumulation of lipids in the tear film may lead to drying of the corneal epithelium. In the circulation, Phospholipid Transfer protein (PLTP) and cholesteryl ester Transfer protein (CETP) mediate lipid Transfers. To gain insight into the formation of tear film, we investigated whether PLTP and CETP are present in human tear fluid. Tear fluid samples were collected with microcapillaries. The presence of PLTP and CETP was studied in tear fluid by Western blotting, and the PLTP concentration was determined by ELISA. The activities of the enzymes were determined by specific lipid Transfer assays. Size-exclusion and heparin-affinity chromatography assessed the molecular form of PLTP. PLTP is present in tear fluid, whereas CETP is not. Quantitative assessment of PLTP by ELISA indicated that the PLTP concentration in tear fluid, 10.9 +/- 2.4 microg/mL, is about 2-fold higher than that in human plasma. PLTP-facilitated Phospholipid Transfer activity in tears, 15.1 +/- 1.8 micromol mL(-)(1) h(-)(1), was also significantly higher than that measured in plasma. Inactivation of PLTP by heat treatment (+58 degrees C, 60 min) or immunoinhibition abolished the Phospholipid Transfer activity in tear fluid. Size-exclusion chromatography of tear fluid indicated that PLTP eluted in a position corresponding to a size of 160-170 kDa. Tear fluid PLTP was quantitatively bound to Heparin-Sepharose and could be eluted as a single peak by 0.5 M NaCl. These data indicate that human tear fluid contains catalytically active PLTP protein, which resembles the active form of PLTP present in plasma. The results suggest that PLTP may play a role in the formation of the tear film by supporting Phospholipid Transfer.
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determination of human plasma Phospholipid Transfer protein mass and activity
Methods, 2005Co-Authors: Matti Jauhiainen, Christian EhnholmAbstract:Plasma Phospholipid Transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP is an 80-kDa glycoprotein that is expressed/secreted by a wide variety of tissues including lung, liver, adipose tissue, brain, and muscle. PLTP mediates a net Transfer of Phospholipids between vesicles and plasma HDLs. It also generates from small HDL particles large fused HDL particles with a concomitant formation of small lipid-poor apolipoprotein (apo) A-I-containing particles which are thought to act as the primary acceptors of cell-derived cholesterol from peripheral tissue macrophages. Another important function of PLTP is connected to lipolysis. Its role in the Transfer of surface remnants from triglyceride-rich particles, very-low-density lipoproteins, and chylomicrons, to HDL is of importance for the maintenance of HDL levels. Recent observations from our laboratory have demonstrated that in circulation two forms of PLTP are present, one catalytically active (high-activity form, HA-PLTP) and the other a low-activity form (LA-PLTP). In view of the likely relevancy of PLTP in human health and disease, reliable and accurate methods for measuring plasma/serum PLTP activity and concentration are required. In this chapter, two radiometric PLTP activity assays are described: (i) exogenous, lipoprotein-independent Phospholipid Transfer assay and (ii) endogenous, lipoprotein-dependent Phospholipid Transfer assay. In addition, an ELISA method for quantitation of serum/plasma total PLTP mass as well as HA-PLTP and LA-PLTP mass is reported in detail.
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Phospholipid Transfer protein is present in human atherosclerotic lesions and is expressed by macrophages and foam cells
Journal of Lipid Research, 2003Co-Authors: Catherine Desrumaux, Christian Ehnholm, Matti Jauhiainen, David Masson, Puiying A Mak, William A Boisvert, Dwayne G Stupack, Linda K CurtissAbstract:Phospholipid Transfer protein (PLTP) in plasma promotes Phospholipid Transfer from triglyceride-rich lipoproteins to HDL and plays a major role in HDL remodeling. Recent in vivo observations also support a key role for PLTP in cholesterol metabolism. Our immunohistochemical analysis of human carotid endarterectomy samples identified immunoreactive PLTP in areas that colocalized with CD68-positive macrophages, suggesting that PLTP could be produced locally by intimal macrophages. Using RT-PCR, Western blot analysis with a monoclonal anti-PLTP antibody, and a PLTP activity assay, we observed PLTP mRNA and protein expression in human macrophages. In adherent peripheral blood human macrophages, this PLTP expression was increased by culture with granulocyte macrophage colony-stimulating factor. Incubation of macrophages with acetylated-LDL induced an increase in PLTP mRNA and protein expression that paralleled cholesterol loading. PLTP expression was observed in elicited mouse peritoneal macrophages and in cultured Raw264.7 cells as well. Thus, this study demonstrates that PLTP is expressed by macrophages, is regulated by cholesterol loading, and is present in atherosclerotic lesions.
John J Albers - One of the best experts on this subject based on the ideXlab platform.
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structural basis of the lipid Transfer mechanism of Phospholipid Transfer protein pltp
Biochimica et Biophysica Acta, 2018Co-Authors: Meng Zhang, John J Albers, Simona Vuletic, Xiaobo Zhai, Gang RenAbstract:Human Phospholipid Transfer protein (PLTP) mediates the Transfer of Phospholipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would represent the first step towards understanding PLTP-mediated lipid Transfers, which may be important for treating lipoprotein abnormalities and cardiovascular disease. Here, using various electron microscopy techniques, PLTP is revealed to have a banana-shaped structure similar to cholesteryl ester Transfer protein (CETP). We provide evidence that PLTP penetrates into the HDL and LDL surfaces, respectively, and then forms a ternary complex with HDL and LDL. Insights into the interaction of PLTP with lipoproteins at the molecular level provide a basis to understand the PLTP-dependent lipid Transfer mechanisms for dyslipidemia treatment.
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inhibition of thrombin generation in human plasma by Phospholipid Transfer protein
Thrombosis Journal, 2015Co-Authors: Hiroshi Deguchi, John J Albers, Marian C Cheung, Gertrud Wolfbauer, Yajnavalka Banerjee, Darlene J Elias, Jose A Fernandez, John H GriffinAbstract:Plasma Phospholipid Transfer protein (PLTP) Transfers lipids between donors and acceptors (e.g., from HDL to VLDL) and modulates lipoprotein composition, size, and levels. No study has reported an assessment of the effects of PLTP on blood clotting reactions, such as reflected in thrombin generation assays, or on the association of venous thrombosis (VTE) risk with PLTP activity. The in vitro effects of PLTP on blood coagulation reactions and the correlations between plasma PLTP activity levels and VTE were studied. Recombinant (r) PLTP concentration-dependently inhibited plasma thrombin generation and factor XII-dependent kallikrein generation when sulfatide was used to stimulate factor XII autoactivation in plasma. However, rPLTP did not inhibit thrombin generation in plasma induced by factor XIa or tissue factor, implicating an effect of PLTP on contact activation reactions. In purified systems, rPLTP inhibited factor XII autoactivation stimulated by sulfatide in the presence of VLDL. In surface plasmon resonance studies, purified factor XII bound to immobilized rPLTP, implying that rPLTP inhibits factor XII-dependent contact activation by binding factor XII in the presence of lipoproteins. Analysis of plasmas from 40 male patients with unprovoked VTE and 40 matched controls indicated that low PLTP lipid Transfer activity (≤25th percentile) was associated with an increased risk of VTE after adjustment for body mass index, plasma lipids, and two known thrombophilic genetic risk factors. These data imply that PLTP may be an antithrombotic plasma protein by inhibiting generation of prothrombotic factor XIIa in the presence of VLDL. This newly discovered anticoagulant activity of PLTP merits further clinical and biochemical studies.
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cerebrospinal fluid apolipoprotein e and Phospholipid Transfer protein activity are reduced in multiple sclerosis relationships with the brain mri and csf lipid variables
Multiple sclerosis and related disorders, 2014Co-Authors: Simona Vuletic, John J Albers, Hal Kennedy, Joep Killestein, Hugo Vrenken, Dieter Lutjohann, Charlotte E TeunissenAbstract:Abstract Apolipoprotein E (apoE), Phospholipid Transfer protein (PLTP) activity, lipids, total tau and beta amyloid 1-42 (Aβ 42 ) were measured in cerebrospinal fluid (CSF) from controls ( n =38) and multiple sclerosis (MS) patients ( n =91). ApoE and PLTP activity were significantly reduced in MS compared to non-inflammatory disease controls (NINDC; p r s =0.399 and 0.591, respectively), Aβ 42 ( r s =0.609 and 0.483, respectively), and total tau ( r s =0.748 and 0.380, respectively; all p p p
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linkage and association of Phospholipid Transfer protein activity to lass4
Journal of Lipid Research, 2011Co-Authors: Elisabeth A Rosenthal, John J Albers, Gertrud Wolfbauer, James Ronald, Joseph H Rothstein, Ramakrishnan Rajagopalan, Jane E Ranchalis, John D Brunzell, Arno G Motulsky, Mark J RiederAbstract:Phospholipid Transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Variation at the PLTP structural locus on chromosome 20 explains some, but not all, heritable variation in PLTPa. In order to detect quantitative trait loci (QTLs) elsewhere in the genome that affect PLTPa, we performed both oligogenic and single QTL linkage analysis on four large families (n = 227 with phenotype, n = 330 with genotype, n = 462 total), ascertained for familial combined hyperlipidemia. We detected evidence of linkage between PLTPa and chromosome 19p (lod = 3.2) for a single family and chromosome 2q (lod = 2.8) for all families. Inclusion of additional marker and exome sequence data in the analysis refined the linkage signal on chromosome 19 and implicated coding variation in LASS4, a gene regulated by leptin that is involved in ceramide synthesis. Association between PLTPa and LASS4 variation was replicated in the other three families (P = 0.02), adjusting for pedigree structure. To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.
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impact of site specific n glycosylation on cellular secretion activity and specific activity of the plasma Phospholipid Transfer protein
Biochimica et Biophysica Acta, 2011Co-Authors: John J Albers, Joseph R Day, Simona Vuletic, Gertrud Wolfbauer, Hal Kennedy, Marian C CheungAbstract:Abstract The plasma Phospholipid Transfer protein (PLTP) plays a key role in lipid and lipoprotein metabolism. It has six potential N-glycosylation sites. To study the impact of these sites on PLTP secretion and activity, six variants containing serine to alanine point mutations were prepared by site-directed mutagenesis and expressed in Chinese hamster ovary Flp-In cells. The apparent size of each of the six PLTP mutants was slightly less than that of wild type by Western blot, indicating that all six sites are glycosylated or utilized. The size of the carbohydrate at each N-glycosylation site ranged from 3.14 to 4.2 kDa. The effect of site-specific N-glycosylation removal on PLTP secretion varied from a modest enhancement (15% and 60%), or essentially no effect, to a reduction in secretion (8%, 14% and 32%). Removal of N-glycosylation at any one of the six glycosylation sites resulted in a significant 35-78% decrease in PLTP activity, and a significant 29-80% decrease in PLTP specific activity compared to wild type. These data indicate that although no single N-linked carbohydrate chain is a requirement for secretion or activity, the removal of the carbohydrate chains had a quantitative impact on cellular secretion of PLTP and its Phospholipid Transfer activity.
Jari Metso - One of the best experts on this subject based on the ideXlab platform.
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ppar β δ activation promotes Phospholipid Transfer protein expression
Biochemical Pharmacology, 2015Co-Authors: Khouloud Chehaibi, Jari Metso, Lidia Cedo, Xavier Palomer, D Santos, Helena Quesada, Mohamed Naceur Slimane, Walter Wahli, Josep Julve, Manuel VazquezcarreraAbstract:The peroxisome proliferator-activated receptor (PPAR)-β/δ has emerged as a promising therapeutic target for treating dyslipidemia, including beneficial effects on HDL cholesterol (HDL-C). In the current study, we determined the effects of the PPAR-β/δ agonist GW0742 on HDL composition and the expression of liver HDL-related genes in mice and cultured human cells. The experiments were carried out in C57BL/6 wild-type, LDL receptor (LDLR)-deficient mice and PPAR-β/δ-deficient mice treated with GW0742 (10mg/kg/day) or a vehicle solution for 14 days. GW0742 upregulated liver Phospholipid Transfer protein (Pltp) gene expression and increased serum PLTP activity in mice. When given to wild-type mice, GW0742 significantly increased serum HDL-C and HDL Phospholipids; GW0742 also raised serum potential to generate preβ-HDL formation. The GW0742-mediated effects on liver Pltp expression and serum enzyme activity were completely abolished in PPAR-β/δ-deficient mice. GW0742 also stimulated PLTP mRNA expression in mouse J774 macrophages, differentiated human THP-1 macrophages and human hepatoma Huh7. Collectively, our findings demonstrate a common transcriptional upregulation by GW0742-activated PPAR-β/δ of Pltp expression in cultured cells and in mouse liver resulting in enhanced serum PLTP activity. Our results also indicate that PPAR-β/δ activation may modulate PLTP-mediated preβ-HDL formation and macrophage cholesterol efflux.
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dry eye symptoms are increased in mice deficient in Phospholipid Transfer protein pltp
American Journal of Pathology, 2011Co-Authors: Niko Setala, Jari Metso, Matti Jauhiainen, Antti Sajantila, Juha M. HolopainenAbstract:In the tear fluid the outermost part facing the tear–air interface is composed of lipids preventing evaporation of the tears. Phospholipid Transfer protein (PLTP) mediates Phospholipid Transfer processes between serum lipoproteins and is also a normal component of human tears. To study whether PLTP plays any functional role in tear fluid we investigated PLTP-deficient mice, applying functional and morphologic analyses under normal housing and experimentally induced dry eye conditions. Aqueous tear fluid production, corneal epithelial morphology, barrier function, and occludin expression were assessed. In mice with a full deficiency of functional PLTP enhanced corneal epithelial damage, increased corneal permeability to carboxyfluorescein, and decreased corneal epithelial occludin expression were shown. These pathologic signs were worsened by experimentally induced dry eye both in wild-type and PLTP knock-out mice. Deficiency in the production of tear PLTP in mice is accompanied by corneal epithelial damage, a feature that is typical in human dry eye syndrome (DES). To complement animal experiments we collected tear fluid from human dry eye patients as well as healthy control subjects. Increased tear fluid PLTP activity was observed among DES patients. In conclusion, the presence of PLTP in tear fluid appears to be essential for maintaining a healthy and functional ocular surface. Increased PLTP activity in human tear fluid in DES patients suggests an ocular surface protective role for this lipid Transfer protein.
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Interaction of Phospholipid Transfer protein with human tear fluid mucins
Journal of lipid research, 2010Co-Authors: Niko L. Setälä, Jari Metso, Ove Eriksson, Juha M. Holopainen, Gebrenegus Yohannes, Jaakko Hiidenhovi, Leif C. Andersson, Alexandra Robciuc, Matti JauhiainenAbstract:In addition to circulation, where it Transfers Phospholipids between lipoprotein particles, Phospholipid Transfer protein (PLTP) was also identified as a component of normal tear fluid. The purpose of this study was to clarify the secretion route of tear fluid PLTP and elucidate possible interactions between PLTP and other tear fluid proteins. Human lacrimal gland samples were stained with monoclonal antibodies against PLTP. Heparin-Sepharose (H-S) affinity chromatography was used for specific PLTP binding, and coeluted proteins were identified with MALDI-TOF mass spectrometry or Western blot analysis. Immunoprecipitation assay and blotting with specific antibodies helped to identify and characterize PLTP-mucin interaction in tear fluid. Human tear fluid PLTP is secreted from the lacrimal gland. MALDI-TOF analysis of H-S fractions identified several candidate proteins, but protein-protein interaction assays revealed only ocular mucins as PLTP interaction partners. We suggest a dual role for PLTP in human tear fluid: (1) to scavenge lipophilic substances from ocular mucins and (2) to maintain the stability of the anterior tear lipid film. PLTP may also play a role in the development of ocular surface disease.
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avian Phospholipid Transfer protein causes hdl conversion without affecting cholesterol efflux from macrophages
WOS, 2009Co-Authors: Jani Saarela, Jari Metso, Wolfgang J Schneider, Matti JauhiainenAbstract:Abstract Circulatory Phospholipid Transfer protein (PLTP) has two major functions: 1) Transfer of Phospholipids towards HDL particles; and 2) modulation of HDL size and composition via the HDL conversion process. In the laying hen (Gallus gallus), the massive oocyte-targeted lipid flow is achieved through the concerted actions of lipases, lipid Transfer proteins, and relatives of the LDL receptor family. The aim of the study was to gain insights into the structure and functions of chicken PLTP. The results demonstrate that PLTP is highly conserved from chicken to mammals, as (i) chicken PLTP is associated with plasma HDL; (ii) it clearly possesses Phospholipid Transfer activity; (iii) it is inactivated at + 58 °C; and (iv) it mediates conversion of avian and human HDL into small preβ-mobile HDL and large fused α-mobile HDL particles. Our data show that HDL from different chicken models is similar in chemical and physical properties to that of man based on PLTP activity, cholesterol efflux, and HDL conversion assays. In contrast to mammals, PLTP-facilitated HDL remodeling did not enhance cholesterol efflux efficiency of chicken HDL particles.
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macrophage Phospholipid Transfer protein contributes significantly to total plasma Phospholipid Transfer activity and its deficiency leads to diminished atherosclerotic lesion development
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: R. Vikstedt, Jari Metso, Christian Ehnholm, Matti Jauhiainen, Reeni B. Hildebrand, Theo J.c. Van Berkel, Miranda Van EckAbstract:Objective— Systemic Phospholipid Transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic lesion development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% ( P <0.01 for difference in lesion area) reduction in aortic root lesion area as compared with mice possessing functional macrophage PLTP (384±36*103 μm2 in the PLTP−M/−M group (n=10), as compared with 539±35*103 μm2 in the PLTP+M/+M group (n=14)) after 9 weeks of Western-type diet feeding. The decreased lesion size in the PLTP−M/−M group coincided with significantly lower serum total cholesterol, free cholesterol, and triglyceride levels in these mice. Furthermore, plasma PLTP activity in the PLTP−M/−M group was 2-fold ( P <0.001) lower than that in the PLTP+M/+M group. Conclusion— Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic lesion development in low-density lipoprotein receptor knockout mice on Western-type diet.