The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Daniel J. Rader - One of the best experts on this subject based on the ideXlab platform.
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abstract 513 Endothelial Lipase is a critical regulator of triglyceride rich lipoprotein clearance
Arteriosclerosis Thrombosis and Vascular Biology, 2019Co-Authors: Cecilia Vitali, John S Millar, Jeffrey T Billheimer, Nicholas J Hand, Daniel J. RaderAbstract:Endothelial Lipase (EL) is a plasma triglyceride (TG) Lipase family member, and a major regulator of HDL metabolism, mainly due to its ability to hydrolyze phospholipids in lipoprotein particles. A...
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abstract 513 Endothelial Lipase is a critical regulator of triglyceride rich lipoprotein clearance
Arteriosclerosis Thrombosis and Vascular Biology, 2019Co-Authors: Cecilia Vitali, John S Millar, Jeffrey T Billheimer, Nicholas J Hand, Daniel J. RaderAbstract:Endothelial Lipase (EL) is a plasma triglyceride (TG) Lipase family member, and a major regulator of HDL metabolism, mainly due to its ability to hydrolyze phospholipids in lipoprotein particles. A...
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Inhibition of Endothelial Lipase Activity by Sphingomyelin in the Lipoproteins
Lipids, 2014Co-Authors: Peng Yang, Daniel J. Rader, John S Hill, Natalia A. Belikova, Jeff Billheimer, Papasani V. SubbaiahAbstract:Endothelial Lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration-dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at the sn-2 position, generating the corresponding PUFA-lyso PtdCho. This specificity for PUFA-PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.
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Lipidomic Analyses of Female Mice Lacking Hepatic Lipase and Endothelial Lipase Indicate Selective Modulation of Plasma Lipid Species
Lipids, 2014Co-Authors: Yanbo Yang, Daniel J. Rader, William R Lagor, Takashi Kuwano, Carolyn J. Albert, Siobhan Brenton, David A. Ford, Robert J BrownAbstract:Hepatic Lipase (HL) and Endothelial Lipase (EL) share overlapping and complementary roles in lipoprotein metabolism. The deletion of HL and EL alleles in mice raises plasma total cholesterol and phospholipid concentrations. However, the influence of HL and EL in vivo on individual molecular species from each class of lipid is not known. We hypothesized that the loss of HL, EL, or both in vivo may affect select molecular species from each class of lipids. To test this hypothesis, we performed lipidomic analyses on plasma and livers from fasted female wild-type, HL-knockout, EL-knockout, and HL/EL-double knockout mice. Overall, the loss of HL, EL, or both resulted in minimal changes to hepatic lipids; however, select species of CE were surprisingly reduced in the livers of mice only lacking EL. The loss of HL, EL, or both reduced the plasma concentrations for select molecular species of triacylglycerol, diacylglycerol, and free fatty acid. On the other hand, the loss of HL, EL, or both raised the plasma concentrations for select molecular species of phosphatidylcholine, cholesteryl ester, diacylglycerol, sphingomyelin, ceramide, plasmanylcholine, and plasmenylcholine. The increased plasma concentration of select ether phospholipids was evident in the absence of EL, thus suggesting that EL might exhibit a phosphoLipase A_2 activity. Using recombinant EL, we showed that it could hydrolyse the artificial phosphoLipase A_2 substrate 4-nitro-3-(octanoyloxy)benzoic acid. In summary, our study shows for the first time the influence of HL and EL on individual molecular species of several classes of lipids in vivo using lipidomic methods.
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Endothelial Lipase is a critical determinant of high density lipoprotein stimulated sphingosine 1 phosphate dependent signaling in vascular endothelium
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Satoru Tatematsu, Daniel J. Rader, Sanjeev A Francis, Pradeep Natarajan, Alan Saghatelian, Jonathan D Brown, Thomas Michel, Jorge PlutzkyAbstract:Objective—In addition to an extensively characterized role of high-density lipoprotein (HDL) in reverse cholesterol transport, bioactive lipids bound to HDL can also exert diverse vascular effects. Despite this, integration of HDL action in the vasculature with pathways that metabolize HDL and release bioactive lipids has been much less explored. The effects of HDL on Endothelial cells are mediated in part by HDL-associated sphingosine 1-phosphate (S1P), which binds to S1P1 receptors and promotes activation of Endothelial NO synthase (eNOS) and the kinase Akt. In these studies, we characterized the role of Endothelial Lipase (EL) in the control of Endothelial signaling and biology, including those mediated by HDL-associated S1P. Approach and Results—HDL-induced angiogenesis in aortic rings from EL-deficient (EL−/−) mice was markedly decreased compared with wild-type controls. In cultured Endothelial cells, small interfering RNA–mediated knockdown of EL abrogated HDL-promoted Endothelial cell migration and...
Uwe J F Tietge - One of the best experts on this subject based on the ideXlab platform.
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role of hepatic Lipase and Endothelial Lipase in high density lipoprotein mediated reverse cholesterol transport
Current Atherosclerosis Reports, 2011Co-Authors: Wijtske Annema, Uwe J F TietgeAbstract: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 macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.
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role of hepatic Lipase and Endothelial Lipase in high density lipoprotein mediated reverse cholesterol transport
Current Atherosclerosis Reports, 2011Co-Authors: Wijtske Annema, Uwe J F TietgeAbstract: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 macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.
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hepatic sr bi not Endothelial Lipase expression determines biliary cholesterol secretion in mice
Journal of Lipid Research, 2009Co-Authors: Harmen Wiersma, Niels Nijstad, Alberto Gatti, Folkert Kuipers, Uwe J F TietgeAbstract:High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an Endothelial Lipase (EL)–mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.
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scavenger receptor bi mediated selective uptake is required for the remodeling of high density lipoprotein by Endothelial Lipase
Journal of Biological Chemistry, 2009Co-Authors: Niels Nijstad, Cyrille Maugeais, Harmen Wiersma, Thomas Gautier, Markus Van Der Giet, Uwe J F TietgeAbstract:Endothelial Lipase (EL) is a negative regulator of high density lipoprotein (HDL) cholesterol plasma levels, and scavenger receptor BI (SR-BI) is involved in remodeling of HDL. The present study investigates the requirement of SR-BI for the effects of EL-mediated phospholipid hydrolysis on HDL metabolism in vivo. In vitro, selective uptake from EL-modified HDL was 129% higher than selective uptake from control HDL in SR-BI-overexpressing cells (p = 0.01). In vivo overexpression of human EL by means of recombinant adenovirus decreased HDL plasma levels significantly (p
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dose dependent acceleration of high density lipoprotein catabolism by Endothelial Lipase
Circulation, 2003Co-Authors: Cyrille Maugeais, Uli Broedl, Dawn Marchadier, Jane M Glick, Mary G Mccoy, Uwe J F Tietge, William Cain, Sissel Lundkatz, Daniel J. RaderAbstract:Background—Factors that regulate the metabolism of HDL and apolipoprotein A-I (apoA-I) are incompletely understood. Overexpression of Endothelial Lipase (EL) markedly reduces plasma levels of HDL cholesterol and apoA-I in mice, but the mechanisms of this effect remain unknown. Methods and Results—We used different doses of a recombinant adenoviral vector to overexpress human EL in mice and studied the effects on plasma phosphoLipase activity, plasma lipids, HDL particle size, HDL turnover, and tissue sites of HDL degradation in mice. Overexpression of EL was associated with a significant dose-dependent increase in postheparin plasma phosphoLipase activity. Plasma phospholipid, HDL cholesterol, and apoA-I levels were markedly decreased, even at the lowest dose of vector. Kinetic studies demonstrated a significant dose-dependent increase in the fractional catabolic rate of HDL-apolipoprotein in EL-overexpressing mice. The postheparin plasma phosphoLipase activity was significantly positively correlated with HDL-apolipoprotein fractional catabolic rate. The uptake of apoA-I by the kidney and the liver was significantly increased by 2.5-fold and 3-fold, respectively, in mice overexpressing EL. Conclusions—Expression of EL in mice results in a dose-dependent increase in postheparin plasma phosphoLipase activity, catabolic rate of HDL-apolipoprotein, and uptake of apoA-I in both kidney and liver. (Circulation. 2003;108:21212126.)
Tatsuro Ishida - One of the best experts on this subject based on the ideXlab platform.
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serum concentration of full length and carboxy terminal fragments of Endothelial Lipase predicts future cardiovascular risks in patients with coronary artery disease
Journal of Clinical Lipidology, 2019Co-Authors: Manabu Nagao, Ken-ichi Hirata, Kazuya Miyashita, Kenta Mori, Katsuyuki Nakajima, Ryuji Toh, Tetsuya Hara, Masakazu Shinohara, Yasuhiro Irino, Tatsuro IshidaAbstract:Background Endothelial Lipase (EL), a regulator of plasma high-density lipoprotein cholesterol (HDL-C), is secreted as a 68-kDa mature glycoprotein, and then cleaved by proprotein convertases. However, the clinical significance of the circulating EL fragments remains unclear. Objective The objective of this study was to analyze the impact of serum EL fragments on HDL-C levels and major adverse cardiovascular events (MACE). Methods Using novel monoclonal antibodies (RC3A6) against carboxy-terminal EL protein, we have established a new enzyme-linked immunosorbent assay (ELISA) system, which can detect both full-length EL protein (full EL) and carboxy-terminal truncated fragments (total EL) in serum. The previous sandwich ELISA detected only full EL. The full and total EL mass were measured in 556 patients with coronary artery disease. Among them, 272 patients who underwent coronary intervention were monitored for 2 years for MACE. Results There was a significant correlation between serum full and total EL mass (R = 0.45, P Conclusion Serum total EL mass could be a predictor for MACE in patients with coronary artery disease. This novel ELISA will be useful for further clarifying the impact of EL on HDL metabolism and atherosclerosis.
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plasma activity of Endothelial Lipase impacts high density lipoprotein metabolism and coronary risk factors in humans
Journal of Atherosclerosis and Thrombosis, 2014Co-Authors: Li Sun, Tomoyuki Yasuda, Tatsuro Ishida, Kazuya Miyashita, Noriaki Kinoshita, Kenta Mori, Shigeyuki Imamura, Katsuyuki Nakajima, Ryuji Toh, Ken-ichi HirataAbstract:Aim Endothelial Lipase (EL) is a determinant of plasma levels of high-density lipoprotein cholesterol (HDL-C). However, little is known about the impact of EL activity on plasma lipid profile. We aimed to establish a new method to evaluate EL-specific phosphoLipase activity in humans. Methods Plasma samples were obtained from 115 patients with coronary artery disease (CAD) and 154 patients without CAD. Plasma EL protein was immunoprecipitated using an anti-EL monoclonal antibody after plasma non-specific immunoglobulins were removed by incubation with ProteinA. The phosphoLipase activity of the immunoprecipitated samples was measured using a fluorogenic phosphoLipase substrate, Bis-BODIPY FL C11-PC. Results The EL-specific phosphoLipase assay revealed that plasma EL activity was inversely correlated with HDL-C levels (R = -0.3088, p＜0.0001). In addition, the EL activity was associated with cigarette smoking. Furthermore, EL activity in CAD patients was significantly higher than that in nonCAD patients. Concomitantly, the HDL-C level in CAD patients were significantly lower than that in non-CAD patients. Conclusion We have established a method for human plasma EL-specific phosphoLipase activity by combination of EL immunoprecipitation and a fluorogenic phospholipid substrate. Plasma EL activity was associated with not only plasma HDL-C levels but also the risks for CAD.
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elisa system for human Endothelial Lipase
Clinical Chemistry, 2012Co-Authors: Tatsuro Ishida, Tomoyuki Yasuda, Kazuya Miyashita, Mamoru Shimizu, Noriaki Kinoshita, Kenta Mori, Li Sun, Shigeyuki Imamura, Katsuyuki Nakajima, Kimber L StanhopeAbstract:BACKGROUND: Endothelial Lipase (EL) regulates the metabolism of HDL cholesterol (HDL-C). However, the role of EL in regulating plasma HDL-C concentrations and EL's potential involvement in atherosclerosis in humans has not been fully investigated due to the lack of reliable assays for EL mass. We developed an ELISA system for serum EL mass. METHODS: Human recombinant EL proteins, purified from cultured media of human EL-transfected CHO cells, were used as antigen and calibrator. Two specific monoclonal antibodies were generated in mice against recombinant EL protein for a sandwich ELISA. We measured EL mass in human serum using EL recombinant protein as a calibration standard. RESULTS: The EL antibodies did not cross-react with lipoprotein Lipase and hepatic triglyceride Lipase. The detection limit of the ELISA was 20 pg/mL, which is approximately 10 times lower than that of previous ELISA systems. Recovery of spiked EL in serum was 90%–105%. Assay linearity was intact with a >4-fold dilution of serum. Intra- and interassay CVs were <5%. The serum EL mass in 645 human subjects was [mean (SE)] 344.4 (7.7) pg/mL (range 55.2–1387.7 pg/mL). Interestingly, serum EL mass was increased in patients with diagnosed cardiovascular disease and inversely correlated with serum HDL-C concentrations. There was no difference in EL mass between pre- and post-heparin plasma samples. CONCLUSIONS: This ELISA should be useful for clarifying the impact of EL on HDL metabolism and EL's potential role in atherosclerosis.
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targeted deletion of Endothelial Lipase increases hdl particles with anti inflammatory properties both in vitro and in vivo
Journal of Lipid Research, 2011Co-Authors: Tetsuya Hara, Tomoyuki Yasuda, Tatsuro Ishida, Yoko Kojima, Hanayo Tanaka, Ryuji Toh, Masakazu Shinohara, Ken-ichi HirataAbstract:Previous studies have shown that targeted deletion of Endothelial Lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL(-/-) and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL(-/-) and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL(-/-) mice. In contrast, the lipopolysaccharide-neutralizing capacity of HDL was significantly higher in EL(-/-) mice than that in WT mice. To evaluate the anti-inflammatory actions of HDL in vivo, lipopolysaccharide-induced systemic inflammation was generated in these mice. EL(-/-) mice showed higher survival rate and lower expression of inflammatory markers than WT mice. Intravenous administration of HDL isolated from EL(-/-) mice significantly improved the mortality after lipopolysaccharide injection in WT mice. In conclusion, targeted disruption of EL increased HDL particles with preserved anti-inflammatory and anti-atherosclerotic functions. Thus, EL inhibition would be a useful strategy to raise 'good' cholesterol in the plasma.
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update on the role of Endothelial Lipase in high density lipoprotein metabolism reverse cholesterol transport and atherosclerosis
Circulation, 2010Co-Authors: Tomoyuki Yasuda, Tatsuro Ishida, Daniel J. RaderAbstract:Endothelial Lipase (EL) is a phosphoLipase that belongs to the lipoprotein Lipase (LPL) family, which includes LPL and hepatic Lipase (HL). Similar to LPL and HL, EL regulates lipoprotein metabolism, mainly high-density lipoprotein (HDL) metabolism and HDL cholesterol (HDL-C) levels in humans and mice. Existing data strongly suggest that inhibition of EL in humans would be expected to increase the HDL-C level. However, it has not been definitively established whether the effect of EL activity on HDL-C levels translates into effects on reverse cholesterol transport or atherosclerosis. The available data regarding the impact of EL expression and activity on HDL metabolism, reverse cholesterol transport, and atherosclerosis are reviewed. (Circ J 2010; 74: 2263-2270)
Tomoyuki Yasuda - One of the best experts on this subject based on the ideXlab platform.
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plasma activity of Endothelial Lipase impacts high density lipoprotein metabolism and coronary risk factors in humans
Journal of Atherosclerosis and Thrombosis, 2014Co-Authors: Li Sun, Tomoyuki Yasuda, Tatsuro Ishida, Kazuya Miyashita, Noriaki Kinoshita, Kenta Mori, Shigeyuki Imamura, Katsuyuki Nakajima, Ryuji Toh, Ken-ichi HirataAbstract:Aim Endothelial Lipase (EL) is a determinant of plasma levels of high-density lipoprotein cholesterol (HDL-C). However, little is known about the impact of EL activity on plasma lipid profile. We aimed to establish a new method to evaluate EL-specific phosphoLipase activity in humans. Methods Plasma samples were obtained from 115 patients with coronary artery disease (CAD) and 154 patients without CAD. Plasma EL protein was immunoprecipitated using an anti-EL monoclonal antibody after plasma non-specific immunoglobulins were removed by incubation with ProteinA. The phosphoLipase activity of the immunoprecipitated samples was measured using a fluorogenic phosphoLipase substrate, Bis-BODIPY FL C11-PC. Results The EL-specific phosphoLipase assay revealed that plasma EL activity was inversely correlated with HDL-C levels (R = -0.3088, p＜0.0001). In addition, the EL activity was associated with cigarette smoking. Furthermore, EL activity in CAD patients was significantly higher than that in nonCAD patients. Concomitantly, the HDL-C level in CAD patients were significantly lower than that in non-CAD patients. Conclusion We have established a method for human plasma EL-specific phosphoLipase activity by combination of EL immunoprecipitation and a fluorogenic phospholipid substrate. Plasma EL activity was associated with not only plasma HDL-C levels but also the risks for CAD.
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elisa system for human Endothelial Lipase
Clinical Chemistry, 2012Co-Authors: Tatsuro Ishida, Tomoyuki Yasuda, Kazuya Miyashita, Mamoru Shimizu, Noriaki Kinoshita, Kenta Mori, Li Sun, Shigeyuki Imamura, Katsuyuki Nakajima, Kimber L StanhopeAbstract:BACKGROUND: Endothelial Lipase (EL) regulates the metabolism of HDL cholesterol (HDL-C). However, the role of EL in regulating plasma HDL-C concentrations and EL's potential involvement in atherosclerosis in humans has not been fully investigated due to the lack of reliable assays for EL mass. We developed an ELISA system for serum EL mass. METHODS: Human recombinant EL proteins, purified from cultured media of human EL-transfected CHO cells, were used as antigen and calibrator. Two specific monoclonal antibodies were generated in mice against recombinant EL protein for a sandwich ELISA. We measured EL mass in human serum using EL recombinant protein as a calibration standard. RESULTS: The EL antibodies did not cross-react with lipoprotein Lipase and hepatic triglyceride Lipase. The detection limit of the ELISA was 20 pg/mL, which is approximately 10 times lower than that of previous ELISA systems. Recovery of spiked EL in serum was 90%–105%. Assay linearity was intact with a >4-fold dilution of serum. Intra- and interassay CVs were <5%. The serum EL mass in 645 human subjects was [mean (SE)] 344.4 (7.7) pg/mL (range 55.2–1387.7 pg/mL). Interestingly, serum EL mass was increased in patients with diagnosed cardiovascular disease and inversely correlated with serum HDL-C concentrations. There was no difference in EL mass between pre- and post-heparin plasma samples. CONCLUSIONS: This ELISA should be useful for clarifying the impact of EL on HDL metabolism and EL's potential role in atherosclerosis.
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targeted deletion of Endothelial Lipase increases hdl particles with anti inflammatory properties both in vitro and in vivo
Journal of Lipid Research, 2011Co-Authors: Tetsuya Hara, Tomoyuki Yasuda, Tatsuro Ishida, Yoko Kojima, Hanayo Tanaka, Ryuji Toh, Masakazu Shinohara, Ken-ichi HirataAbstract:Previous studies have shown that targeted deletion of Endothelial Lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL(-/-) and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL(-/-) and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL(-/-) mice. In contrast, the lipopolysaccharide-neutralizing capacity of HDL was significantly higher in EL(-/-) mice than that in WT mice. To evaluate the anti-inflammatory actions of HDL in vivo, lipopolysaccharide-induced systemic inflammation was generated in these mice. EL(-/-) mice showed higher survival rate and lower expression of inflammatory markers than WT mice. Intravenous administration of HDL isolated from EL(-/-) mice significantly improved the mortality after lipopolysaccharide injection in WT mice. In conclusion, targeted disruption of EL increased HDL particles with preserved anti-inflammatory and anti-atherosclerotic functions. Thus, EL inhibition would be a useful strategy to raise 'good' cholesterol in the plasma.
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update on the role of Endothelial Lipase in high density lipoprotein metabolism reverse cholesterol transport and atherosclerosis
Circulation, 2010Co-Authors: Tomoyuki Yasuda, Tatsuro Ishida, Daniel J. RaderAbstract:Endothelial Lipase (EL) is a phosphoLipase that belongs to the lipoprotein Lipase (LPL) family, which includes LPL and hepatic Lipase (HL). Similar to LPL and HL, EL regulates lipoprotein metabolism, mainly high-density lipoprotein (HDL) metabolism and HDL cholesterol (HDL-C) levels in humans and mice. Existing data strongly suggest that inhibition of EL in humans would be expected to increase the HDL-C level. However, it has not been definitively established whether the effect of EL activity on HDL-C levels translates into effects on reverse cholesterol transport or atherosclerosis. The available data regarding the impact of EL expression and activity on HDL metabolism, reverse cholesterol transport, and atherosclerosis are reviewed. (Circ J 2010; 74: 2263-2270)
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impact of combined deficiency of hepatic Lipase and Endothelial Lipase on the metabolism of both high density lipoproteins and apolipoprotein b containing lipoproteins
Circulation Research, 2010Co-Authors: Robert J Brown, Tomoyuki Yasuda, Thomas Quertermous, William R Lagor, Sandhya Sankaranaravanan, George H Rothblat, Daniel J. RaderAbstract:Rationale:Hepatic Lipase (HL) and Endothelial Lipase (EL) are extracellular Lipases that both hydrolyze triglycerides and phospholipids and display potentially overlapping or complementary roles in...
Ken-ichi Hirata - One of the best experts on this subject based on the ideXlab platform.
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serum concentration of full length and carboxy terminal fragments of Endothelial Lipase predicts future cardiovascular risks in patients with coronary artery disease
Journal of Clinical Lipidology, 2019Co-Authors: Manabu Nagao, Ken-ichi Hirata, Kazuya Miyashita, Kenta Mori, Katsuyuki Nakajima, Ryuji Toh, Tetsuya Hara, Masakazu Shinohara, Yasuhiro Irino, Tatsuro IshidaAbstract:Background Endothelial Lipase (EL), a regulator of plasma high-density lipoprotein cholesterol (HDL-C), is secreted as a 68-kDa mature glycoprotein, and then cleaved by proprotein convertases. However, the clinical significance of the circulating EL fragments remains unclear. Objective The objective of this study was to analyze the impact of serum EL fragments on HDL-C levels and major adverse cardiovascular events (MACE). Methods Using novel monoclonal antibodies (RC3A6) against carboxy-terminal EL protein, we have established a new enzyme-linked immunosorbent assay (ELISA) system, which can detect both full-length EL protein (full EL) and carboxy-terminal truncated fragments (total EL) in serum. The previous sandwich ELISA detected only full EL. The full and total EL mass were measured in 556 patients with coronary artery disease. Among them, 272 patients who underwent coronary intervention were monitored for 2 years for MACE. Results There was a significant correlation between serum full and total EL mass (R = 0.45, P Conclusion Serum total EL mass could be a predictor for MACE in patients with coronary artery disease. This novel ELISA will be useful for further clarifying the impact of EL on HDL metabolism and atherosclerosis.
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plasma activity of Endothelial Lipase impacts high density lipoprotein metabolism and coronary risk factors in humans
Journal of Atherosclerosis and Thrombosis, 2014Co-Authors: Li Sun, Tomoyuki Yasuda, Tatsuro Ishida, Kazuya Miyashita, Noriaki Kinoshita, Kenta Mori, Shigeyuki Imamura, Katsuyuki Nakajima, Ryuji Toh, Ken-ichi HirataAbstract:Aim Endothelial Lipase (EL) is a determinant of plasma levels of high-density lipoprotein cholesterol (HDL-C). However, little is known about the impact of EL activity on plasma lipid profile. We aimed to establish a new method to evaluate EL-specific phosphoLipase activity in humans. Methods Plasma samples were obtained from 115 patients with coronary artery disease (CAD) and 154 patients without CAD. Plasma EL protein was immunoprecipitated using an anti-EL monoclonal antibody after plasma non-specific immunoglobulins were removed by incubation with ProteinA. The phosphoLipase activity of the immunoprecipitated samples was measured using a fluorogenic phosphoLipase substrate, Bis-BODIPY FL C11-PC. Results The EL-specific phosphoLipase assay revealed that plasma EL activity was inversely correlated with HDL-C levels (R = -0.3088, p＜0.0001). In addition, the EL activity was associated with cigarette smoking. Furthermore, EL activity in CAD patients was significantly higher than that in nonCAD patients. Concomitantly, the HDL-C level in CAD patients were significantly lower than that in non-CAD patients. Conclusion We have established a method for human plasma EL-specific phosphoLipase activity by combination of EL immunoprecipitation and a fluorogenic phospholipid substrate. Plasma EL activity was associated with not only plasma HDL-C levels but also the risks for CAD.
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targeted deletion of Endothelial Lipase increases hdl particles with anti inflammatory properties both in vitro and in vivo
Journal of Lipid Research, 2011Co-Authors: Tetsuya Hara, Tomoyuki Yasuda, Tatsuro Ishida, Yoko Kojima, Hanayo Tanaka, Ryuji Toh, Masakazu Shinohara, Ken-ichi HirataAbstract:Previous studies have shown that targeted deletion of Endothelial Lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL(-/-) and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL(-/-) and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL(-/-) mice. In contrast, the lipopolysaccharide-neutralizing capacity of HDL was significantly higher in EL(-/-) mice than that in WT mice. To evaluate the anti-inflammatory actions of HDL in vivo, lipopolysaccharide-induced systemic inflammation was generated in these mice. EL(-/-) mice showed higher survival rate and lower expression of inflammatory markers than WT mice. Intravenous administration of HDL isolated from EL(-/-) mice significantly improved the mortality after lipopolysaccharide injection in WT mice. In conclusion, targeted disruption of EL increased HDL particles with preserved anti-inflammatory and anti-atherosclerotic functions. Thus, EL inhibition would be a useful strategy to raise 'good' cholesterol in the plasma.
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role of Endothelial Lipase in plasma hdl levels in a murine model of hypertriglyceridemia
Journal of Atherosclerosis and Thrombosis, 2009Co-Authors: Hanayo Tanaka, Tomoyuki Yasuda, Thomas Quertermous, Tatsuro Ishida, Ramendra K Kundu, Yoko Kojima, Thomas P Johnston, Tomomi Ueyama, Yuichi Ishikawa, Ken-ichi HirataAbstract:Aim: Hypertriglyceridemia is the most common cause of low plasma high-density lipoprotein cholesterol (HDL-C) levels; however, the correlation between high triglyceride (TG) and low HDL-C remains unclear. Endothelial Lipase (EL) is a determinant of plasma HDL levels. We investigated the role of EL in HDL metabolism in a murine model of acute hypertriglyceridemia.Methods and Results: To establish TG-dominant hyperlipidemia, EL-/- and wild-type (WT) mice were injected with Poloxamer-407 (P-407, 0.5 g/kg, i.p.). A single injection of P-407 resulted in a marked increase in plasma TG and cholesterol levels together with a decrease in HDL-C levels. Although plasma TG levels were similar in EL-/- and WT mice after P-407 injection, HDL-C levels were 80% higher and the HDL particle size was significantly larger in EL-/- mice than in WT mice. P-407 treatment inhibited plasma lipoprotein Lipase activity and EL phosphoLipase activity, without decreasing their expressions. Adenovirus-mediated overexpression of EL in the liver reduced plasma HDL-C levels in both normo- and hyperlipidemic mice, while overexpression of catalytically inactive EL reduced HDL-C levels in hyperlipidemic mice. Cell culture experiments revealed that both catalytically active and inactive EL promoted cellular HDL uptake to the same extent.Conclusion: EL regulates plasma HDL levels in mice in the normolipidemic as well as the acute hypertriglyceridemic state. EL can modulate plasma HDL-CHOL levels through both its lipolytic and ligand-binding functions in hypertriglyceridemic mice, while lipolytic activity appears to be the main determinant for its effects on HDL metabolism in normolipidemic mice.
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targeted inactivation of Endothelial Lipase attenuates lung allergic inflammation through raising plasma hdl level and inhibiting eosinophil infiltration
American Journal of Physiology-lung Cellular and Molecular Physiology, 2009Co-Authors: Hiroshi Otera, Tomoyuki Yasuda, Thomas Quertermous, Tatsuro Ishida, Ken-ichi Hirata, Ramendra K Kundu, Teruaki Nishiuma, Kazuyuki Kobayashi, Yoshikazu Kotani, Yoshihiro NishimuraAbstract:Endothelial Lipase (EL) is a novel phosphoLipase that determines plasma high-density lipoprotein cholesterol (HDL-C) levels. We have investigated the role of HDL-C in lung allergic inflammation by using EL knockout (EL-KO) mice that are high in HDL-C. EL-KO and wild-type control mice were sensitized and challenged with ovalbumin to evoke eosinophilic inflammation in the lung. EL was expressed in epithelial cells, alveolar type II cells, and Endothelial cells in the lung, and its expression was upregulated during inflammation. Concomitant with attenuated hyperresponsiveness of the airway smooth muscles, the number of eosinophils in bronchoalveolar lavage and the expression of VCAM-1 were lower in EL-KO mice than in control mice. HDL reduced cytokine-induced VCAM-1 expression in cultured Endothelial cells. When plasma HDL levels were decreased to similar levels in both mouse groups by adenovirus-mediated overexpression of EL, however, eosinophil infiltration was still lower in EL-KO mice. In vitro adhesion assays revealed that EL expression on the cell surface promoted the interaction of eosinophils through the ligand-binding function of EL. In summary, targeted inactivation of EL attenuated allergic inflammation in the lung, and the protective effects in EL-KO mice were associated with high plasma HDL levels, downregulation of VCAM-1, and loss of the direct ligand-binding function of EL. Thus EL is a novel modulator of the progression of allergic asthma.