The Experts below are selected from a list of 3669 Experts worldwide ranked by ideXlab platform
Matti Jauhiainen - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
the role of Phospholipid Transfer Protein in lipoProtein mediated neutralization of the procoagulant effect of anionic liposomes
Journal of Thrombosis and Haemostasis, 2010Co-Authors: Cecilia Oslakovic, Matti Jauhiainen, Christian EhnholmAbstract:Summary Background: Serum has the ability to neutralize the procoagulant properties of anionic liposomes, with Transfer of Phospholipids (PLs) to both high-density lipoProtein (HDL) and low-density lipoProtein (LDL) particles. Phospholipid Transfer Protein (PLTP) mediates Transfer of PLs between HDL and other lipoProteins and conversion of HDL into larger and smaller particles. Objectives: To examine the role of PLTP in the neutralization of procoagulant liposomes. Methods: Procoagulant liposomes were incubated with different lipoProteins in the presence or absence of PLTP, and then tested for their ability to stimulate thrombin formation. Results and Conclusions: In the absence of added PLTP, the lipoProtein-enriched fraction, total HDL, HDL(3) and very high-density lipoProtein (VHDL) were all able to neutralize the procoagulant properties of the liposomes. In these samples, endogenous PLTP was present, as judged by western blotting. In contrast, no PLTP was present in LDL, HDL(2) and lipoProtein-deficient serum, all of which displayed no ability to neutralize the procoagulant liposomes. The Phospholipid (PL) Transfer activity was dependent on both enzyme (PLTP) and PL acceptor (lipoProteins). After treatment of the VHDL fraction with antiserum against PLTP, the neutralization of procoagulant activity was reduced, but could be regained by the addition of active PLTP. The neutralizing activity was dependent on a catalytically active form of PLTP, and addition of a low activity form of PLTP had no effect. In conclusion, PLTP was found to mediate Transfer of anionic PLs to HDL and LDL, thereby neutralizing the effect of procoagulant liposomes resulting in a reduction of procoagulant activity. (Less)
-
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.
-
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.
Christian Ehnholm - One of the best experts on this subject based on the ideXlab platform.
-
the role of Phospholipid Transfer Protein in lipoProtein mediated neutralization of the procoagulant effect of anionic liposomes
Journal of Thrombosis and Haemostasis, 2010Co-Authors: Cecilia Oslakovic, Matti Jauhiainen, Christian EhnholmAbstract:Summary Background: Serum has the ability to neutralize the procoagulant properties of anionic liposomes, with Transfer of Phospholipids (PLs) to both high-density lipoProtein (HDL) and low-density lipoProtein (LDL) particles. Phospholipid Transfer Protein (PLTP) mediates Transfer of PLs between HDL and other lipoProteins and conversion of HDL into larger and smaller particles. Objectives: To examine the role of PLTP in the neutralization of procoagulant liposomes. Methods: Procoagulant liposomes were incubated with different lipoProteins in the presence or absence of PLTP, and then tested for their ability to stimulate thrombin formation. Results and Conclusions: In the absence of added PLTP, the lipoProtein-enriched fraction, total HDL, HDL(3) and very high-density lipoProtein (VHDL) were all able to neutralize the procoagulant properties of the liposomes. In these samples, endogenous PLTP was present, as judged by western blotting. In contrast, no PLTP was present in LDL, HDL(2) and lipoProtein-deficient serum, all of which displayed no ability to neutralize the procoagulant liposomes. The Phospholipid (PL) Transfer activity was dependent on both enzyme (PLTP) and PL acceptor (lipoProteins). After treatment of the VHDL fraction with antiserum against PLTP, the neutralization of procoagulant activity was reduced, but could be regained by the addition of active PLTP. The neutralizing activity was dependent on a catalytically active form of PLTP, and addition of a low activity form of PLTP had no effect. In conclusion, PLTP was found to mediate Transfer of anionic PLs to HDL and LDL, thereby neutralizing the effect of procoagulant liposomes resulting in a reduction of procoagulant activity. (Less)
-
Cholesterol efflux from macrophage foam cells is enhanced by active Phospholipid Transfer Protein through generation of two types of acceptor particles
Biochemistry, 2007Co-Authors: R. Vikstedt, Jari Metso, Jukka Hakala, Christian Ehnholm, Vesa M Olkkonen, Matti JauhiainenAbstract:Phospholipid Transfer Protein (PLTP) is expressed by macrophage-derived foam cells in human atherosclerotic lesions, suggesting a regulatory role for PLTP in cellular cholesterol homeostasis. However, the exact role of PLTP in the reverse cholesterol transport pathway is not known. PLTP is present in plasma as two forms, a highly active (HA-PLTP) and a lowly active (LA-PLTP) form. In this study we clarify the role of the two forms of PLTP in cholesterol efflux from [3H]cholesterol oleate−acetyl-LDL-loaded THP-1 macrophages. Incubation of HDL in the presence of HA-PLTP resulted in the formation of two types of acceptor particles, preβ-HDL and large fused HDL. HA-PLTP increased preβ-HDL formation and caused a 42% increase in [3H]cholesterol efflux to HDL, while LA-PLTP neither formed preβ-HDL nor increased cholesterol efflux. Removal of the formed preβ-HDL by immunoprecipitation decreased cholesterol efflux by 47%. Neither HA- nor LA-PLTP enhanced cholesterol efflux to lipid-free apoA-I. Importantly, also t...
-
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.
-
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.
-
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.
Xiancheng Jiang - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
the binding capability of plasma Phospholipid Transfer Protein but not hdl pool size is critical to repress lps induced inflammation
Scientific Reports, 2016Co-Authors: Yingjie Cui, Yanan Zhao, Shuai Liu, Guohua Song, Peng Jiao, Tian Luo, Shoudong Guo, Xiangjian Zhang, Hao Wang, Xiancheng JiangAbstract:Phospholipid Transfer Protein (PLTP) participates in high density lipoProtein (HDL) metabolism. Increased plasma PLTP activity was observed in lipopolysaccharide (LPS) triggered acute inflammatory diseases. This study aimed to determine the exact role of PLTP in LPS induced inflammation. HDL pool size was shrunk both in PLTP deficient mice (PLTP-/-) and PLTP transgenic mice (PLTP-Tg). PLTP displayed a strong protective effect on lethal endotoxemia in mice survival study. Furthermore, after LPS stimulation, the expression of pro-inflammatory cytokines were increased in bone marrow derived macrophage (BMDM) from PLTP-/-, while decreased in BMDM from PLTP-Tg compared with BMDM from wild-type mice (WT). Moreover, LPS induced nuclear factor kappa-B (NFκB) activation was enhanced in PLTP-/- BMDM or PLTP knockdown RAW264.7. Conversely, PLTP overexpression countered the NFκB activation in LPS challenged BMDM. Additionally, the activation of toll like receptor 4 (TLR4) induced by LPS showed no alteration in PLTP-/- BMDM. Finally, PLTP could bind to LPS, attenuate the pro-inflammatory effects of LPS, and improve the cell viability in vitro. To sum up, these findings elucidated that PLTP repressed LPS induced inflammation due to extracellular LPS binding capability, and the protective effects were not related to HDL pool size in mice.
-
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
John J Albers - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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
-
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.
-
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.
Laurent Lagrost - One of the best experts on this subject based on the ideXlab platform.
-
intra abdominal lipopolysaccharide clearance and inactivation in peritonitis key roles for lipoProteins and the Phospholipid Transfer Protein
Frontiers in Immunology, 2021Co-Authors: Maxime Nguyen, Laurent Lagrost, Naig Le Guern, Gaetan Pallot, Antoine Jalil, Annabelle Tavernier, Alois Dusuel, Jeanpaul Pais De Barros, Helene Choubley, Victoria BergasAbstract:Introduction During peritonitis, lipopolysaccharides (LPS) cross the peritoneum and pass through the liver before reaching the central compartment. The aim of the present study was to investigate the role of lipoProteins and Phospholipid Transfer Protein (PLTP) in the early stages of LPS detoxification. Material and Methods Peritonitis was induced by intra-peritoneal injection of LPS in mice. We analyzed peritoneal fluid, portal and central blood. LipoProtein fractions were obtained by ultracentrifugation and fast Protein liquid chromatography. LPS concentration and activity were measured by liquid chromatography coupled with mass spectrometry and limulus amoebocyte lysate. Wild-type mice were compared to mice knocked out for PLTP. Results In mice expressing PLTP, LPS was able to bind to HDL in the peritoneal compartment, and this was maintained in plasma from portal and central blood. A hepatic first-pass effect of HDL-bound LPS was observed in wild-type mice. LPS binding to HDL resulted in an early arrival of inactive LPS in the central blood of wild-type mice. Conclusion PLTP promotes LPS peritoneal clearance and neutralization in a model of peritonitis. This mechanism involves the early binding of LPS to lipoProteins inside the peritoneal cavity, which promotes LPS translocation through the peritoneum and its uptake by the liver.
-
Increased Amyloid-β Peptide-Induced Memory Deficits in Phospholipid Transfer Protein (PLTP) Gene Knockout Mice
Neuropsychopharmacology, 2013Co-Authors: Catherine Desrumaux, Anne Athias, Laurent Lagrost, Valerie Deckert, Amandine Pisoni, Johann Meunier, Véronique Perrier, Vanessa Villard, Jean-michel Verdier, Tangui MauriceAbstract:Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer’s disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma Phospholipid Transfer Protein (PLTP) has a major role in vitamin E Transfers in vivo , and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo , we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid- β _25–35 (A β _25–35) peptide, a non-transgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain A β _1–42 levels, and a lower expression of the synaptic function marker synaptophysin, as compared with wild-type mice. This PLTP-KO phenotype was associated with increased memory impairment 1 week after A β _25–35 peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented A β _25–35-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies.
-
plasma pltp Phospholipid Transfer Protein an emerging role in reverse lipopolysaccharide transport and innate immunity
Biochemical Society Transactions, 2011Co-Authors: Thomas Gautier, Laurent LagrostAbstract:Plasma PLTP (Phospholipid-Transfer Protein) is a member of the lipid Transfer/LBP [LPS (lipopolysaccharide)-binding Protein] family, which constitutes a superfamily of genes together with the short and long PLUNC (palate, lung and nasal epithelium clone) Proteins. Although PLTP was studied initially for its involvement in the metabolism of HDL (high-density lipoProteins) and reverse cholesterol transport (i.e. the metabolic pathway through which cholesterol excess can be transported from peripheral tissues back to the liver for excretion in the bile), it displays a number of additional biological properties. In particular, PLTP can modulate the lipoProtein association and metabolism of LPS that are major components of Gram-negative bacteria. The delayed association of LPS with lipoProteins in PLTP-deficient mice results in a prolonged residence time, in a higher toxicity of LPS aggregates and in a significant increase in LPS-induced mortality as compared with wild-type mice. It suggests that PLTP may play a pivotal role in inflammation and innate immunity through its ability to accelerate the 'reverse LPS transport' pathway.
-
plasma Phospholipid Transfer Protein pltp review of an emerging cardiometabolic risk factor
Obesity Reviews, 2009Co-Authors: T Tzotzas, C Desrumaux, Laurent LagrostAbstract:Plasma Phospholipid Transfer Protein (PLTP) is a lipid Transfer glycoProtein that binds to and Transfers a number of amphipathic compounds. In earlier studies, the attention of the scientific community focused on the positive role of PLTP in high-density lipoProtein (HDL) metabolism. However, this potentially anti-atherogenic role of PLTP has been challenged recently by another picture: PLTP arose as a pro-atherogenic factor through its ability to increase the production of apolipoProtein B-containing lipoProteins, to decrease their antioxidative protection and to trigger inflammation. In humans, PLTP has mostly been studied in patients with cardiometabolic disorders. Both PLTP and related cholesteryl ester Transfer Protein (CETP) are secreted Proteins, and adipose tissue is an important contributor to the systemic pools of these two Proteins. Coincidently, high levels of PLTP and CETP have been found in the plasma of obese patients. PLTP activity and mass have been reported to be abnormally elevated in type 2 diabetes mellitus (T2DM) and insulin-resistant states, and this elevation is frequently associated with hypertriglyceridemia and obesity. This review article presents the state of knowledge on the implication of PLTP in lipoProtein metabolism, on its atherogenic potential, and the complexity of its implication in obesity, insulin resistance and T2DM.
-
atheroprotective potential of macrophage derived Phospholipid Transfer Protein in low density lipoProtein receptor deficient mice is overcome by apolipoProtein ai overexpression
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: David T Valenta, Laurent Lagrost, Nicolas Ogier, Gary Bradshaw, Audrey S Black, David J Bonnet, Linda K Curtiss, Catherine DesrumauxAbstract:Objective— Using bone marrow transplantation, we assessed the impact of macrophage-derived Phospholipid Transfer Protein (PLTP) on lesion development in hypercholesterolemic mice that expressed eit...