Marsche G

References (10)

Title : Associations between Endothelial Lipase, High-Density Lipoprotein, and Endothelial Function Differ in Healthy Volunteers and Metabolic Syndrome Patients - Klobucar_2023_Int.J.Mol.Sci_24_2073
Author(s) : Klobucar I , Stadler JT , Klobucar L , Lechleitner M , Trbusic M , Pregartner G , Berghold A , Habisch H , Madl T , Marsche G , Frank S , Degoricija V
Ref : Int J Mol Sci , 24 :2073 , 2023
Abstract : Metabolic syndrome (MS) is characterized by endothelial- and high-density lipoprotein (HDL) dysfunction and increased endothelial lipase (EL) serum levels. We examined the associations between EL serum levels, HDL (serum levels, lipid content, and function), and endothelial function in healthy volunteers (HV) and MS patients. Flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), serum levels of HDL subclasses (measured by nuclear magnetic resonance (NMR) spectroscopy), and EL serum levels differed significantly between HV and MS patients. The serum levels of triglycerides in large HDL particles were significantly positively correlated with FMD and NMD in HV, but not in MS patients. Cholesterol (C) and phospholipid (PL) contents of large HDL particles, calculated as HDL1-C/HDL1-apoA-I and HDL1-PL/HDL1-apoA-I, respectively, were significantly negatively correlated with FMD in HV, but not in MS patients. Cholesterol efflux capacity and arylesterase activity of HDL, as well as EL, were correlated with neither FMD nor NMD. EL was significantly negatively correlated with HDL-PL/HDL-apoA-I in HV, but not in MS patients, and with serum levels of small dense HDL containing apolipoprotein A-II in MS patients, but not in HV. We conclude that MS modulates the association between HDL and endothelial function, as well as between EL and HDL. HDL cholesterol efflux capacity and arylesterase activity, as well as EL serum levels, are not associated with endothelial function in HV or MS patients.
ESTHER : Klobucar_2023_Int.J.Mol.Sci_24_2073
PubMedSearch : Klobucar_2023_Int.J.Mol.Sci_24_2073
PubMedID: 36768410
Gene_locus related to this paper: human-LIPG

Title : Endothelial Lipase Modulates Paraoxonase 1 Content and Arylesterase Activity of HDL - Schilcher_2021_Int.J.Mol.Sci_22_
Author(s) : Schilcher I , Stadler JT , Lechleitner M , Hrzenjak A , Berghold A , Pregartner G , Lhomme M , Holzer M , Korbelius M , Reichmann F , Springer A , Wadsack C , Madl T , Kratky D , Kontush A , Marsche G , Frank S
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Endothelial lipase (EL) is a strong modulator of the high-density lipoprotein (HDL) structure, composition, and function. Here, we examined the impact of EL on HDL paraoxonase 1 (PON1) content and arylesterase (AE) activity in vitro and in vivo. The incubation of HDL with EL-overexpressing HepG2 cells decreased HDL size, PON1 content, and AE activity. The EL modification of HDL did not diminish the capacity of HDL to associate with PON1 when EL-modified HDL was incubated with PON1-overexpressing cells. The overexpression of EL in mice significantly decreased HDL serum levels but unexpectedly increased HDL PON1 content and HDL AE activity. Enzymatically inactive EL had no effect on the PON1 content of HDL in mice. In healthy subjects, EL serum levels were not significantly correlated with HDL levels. However, HDL PON1 content was positively associated with EL serum levels. The EL-induced changes in the HDL-lipid composition were not linked to the HDL PON1 content. We conclude that primarily, the interaction of enzymatically active EL with HDL, rather than EL-induced alterations in HDL size and composition, causes PON1 displacement from HDL in vitro. In vivo, the EL-mediated reduction of HDL serum levels and the consequently increased PON1-to-HDL ratio in serum increase HDL PON1 content and AE activity in mice. In humans, additional mechanisms appear to underlie the association of EL serum levels and HDL PON1 content.
ESTHER : Schilcher_2021_Int.J.Mol.Sci_22_
PubMedSearch : Schilcher_2021_Int.J.Mol.Sci_22_
PubMedID: 33450841

Title : Endothelial lipase increases eNOS activating capacity of high-density lipoprotein - Radulovic_2020_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1865_158612
Author(s) : Radulovic S , Gottschalk B , Horl G , Zardoya-Laguardia P , Schilcher I , Hallstrom S , Vujic N , Schmidt K , Trieb M , Graier WF , Malli R , Kratky D , Marsche G , Frank S
Ref : Biochimica & Biophysica Acta Molecular & Cellular Biology Lipids , 1865 :158612 , 2020
Abstract : Endothelial lipase (EL) changes structural and functional properties of high-density lipoprotein (HDL). HDL is a relevant modulator of endothelial nitric oxide synthase (eNOS) activity, but the effect of EL on HDL induced eNOS-activation has not yet been investigated. Here, we examined the impact of EL-modified HDL (EL-HDL) on eNOS activity, subcellular trafficking, and eNOS- dependent vasorelaxation. EL-HDL and empty virus (EV)-HDL as control were isolated from human serum incubated with EL-overexpressing or EV infected HepG2 cells. EL-HDL exhibited higher capacity to induce eNOS phosphorylation at Ser1177 and eNOS activity in EA.hy 926 cells, as well as eNOS-dependent vasorelaxation of mouse aortic rings compared to control HDL. As revealed by confocal and structured illumination-microscopy EL-HDL-driven induction of eNOS was accompanied by an increased eNOS-GFP targeting to the plasma membrane and a lower eNOS-GFP colocalization with Golgi and mitochondria. Widefield microscopy of filipin stained cells revealed that EL-HDL lowered cellular free cholesterol (FC) and as found by thin-layer chromatography increased cellular cholesterol ester (CE) content. Additionally, cholesterol efflux capacity, acyl-coenzyme A: cholesterol acyltransferase activity, and HDL particle uptake were comparable between EL-HDL and control HDL. In conclusion, EL increases eNOS activating capacity of HDL, a phenomenon accompanied by an enrichment of the plasma membrane eNOS pool, a decreased cell membrane FC and increased cellular CE content.
ESTHER : Radulovic_2020_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1865_158612
PubMedSearch : Radulovic_2020_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1865_158612
PubMedID: 31923467

Title : Metabolic disease and ABHD6 alter the circulating bis(monoacylglycerol)phosphate profile in mice and humans - Grabner_2019_J.Lipid.Res_60_1020
Author(s) : Grabner GF , Fawzy N , Pribasnig MA , Trieb M , Taschler U , Holzer M , Schweiger M , Wolinski H , Kolb D , Horvath A , Breinbauer R , Rulicke T , Rabl R , Lass A , Stadlbauer V , Hutter-Paier B , Stauber RE , Fickert P , Zechner R , Marsche G , Eichmann TO , Zimmermann R
Ref : J Lipid Res , 60 :1020 , 2019
Abstract : Bis(monoacylglycerol)phosphate (BMP) is a phospholipid that is crucial for lipid degradation and sorting in acidic organelles. Genetic and drug-induced lysosomal storage disorders (LSDs) are associated with increased BMP concentrations in tissues and in the circulation. Data on BMP in disorders other than LSDs, however, are scarce, and key enzymes regulating BMP metabolism remain elusive. Here, we demonstrate that common metabolic disorders and the intracellular BMP hydrolase alpha/beta-hydrolase domain-containing 6 (ABHD6) affect BMP metabolism in mice and humans. In mice, dietary lipid overload strongly affects BMP concentration and FA composition in the liver and plasma, similar to what has been observed in LSDs. Notably, distinct changes in the BMP FA profile enable a clear distinction between lipid overload and drug-induced LSDs. Global deletion of ABHD6 increases circulating BMP concentrations but does not cause LSDs. In humans, nonalcoholic fatty liver disease and liver cirrhosis affect the serum BMP FA composition and concentration. Furthermore, we identified a patient with a loss-of-function mutation in the ABHD6 gene, leading to an altered circulating BMP profile. In conclusion, our results suggest that common metabolic diseases and ABHD6 affect BMP metabolism in mice and humans.
ESTHER : Grabner_2019_J.Lipid.Res_60_1020
PubMedSearch : Grabner_2019_J.Lipid.Res_60_1020
PubMedID: 30894461
Gene_locus related to this paper: human-ABHD6

Title : Impact of Endothelial Lipase on Cholesterol Efflux Capacity of Serum and High-density Lipoprotein - Schilcher_2017_Sci.Rep_7_12485
Author(s) : Schilcher I , Kern S , Hrzenjak A , Eichmann TO , Stojakovic T , Scharnagl H , Duta-Mare M , Kratky D , Marsche G , Frank S
Ref : Sci Rep , 7 :12485 , 2017
Abstract : Endothelial lipase (EL) is a potent modulator of the structural and functional properties of HDL. Impact of EL on cholesterol efflux capacity (CEC) of serum and isolated HDL is not well understood and apparently contradictory data were published. Here, we systematically examined the impact of EL on composition and CEC of serum and isolated HDL, in vitro and in vivo, using EL-overexpressing cells and EL-overexpressing mice. CEC was examined in a validated assay using 3H-cholesterol labelled J774 macrophages. In vitro EL-modification of serum resulted in complex alterations, including enrichment of serum with lipid-free/-poor apoA-I, decreased size of human (but not mouse) HDL and altered HDL lipid composition. EL-modification of serum increased CEC, in line with increased lipid-free/-poor apoA-I formation. In contrast, CEC of isolated HDL was decreased likely through altered lipid composition. In contrast to in vitro results, EL-overexpression in mice markedly decreased HDL-cholesterol and apolipoprotein A-I serum levels associated with a decreased CEC of serum. HDL lipid composition was altered, but HDL particle size and CEC were not affected. Our study highlights the multiple and complex effects of EL on HDL composition and function and may help to clarify the seemingly contradictory data found in published articles.
ESTHER : Schilcher_2017_Sci.Rep_7_12485
PubMedSearch : Schilcher_2017_Sci.Rep_7_12485
PubMedID: 28970555

Title : Liver disease alters high-density lipoprotein composition, metabolism and function - Trieb_2016_Biochim.Biophys.Acta_1861_630
Author(s) : Trieb M , Horvath A , Birner-Gruenberger R , Spindelboeck W , Stadlbauer V , Taschler U , Curcic S , Stauber RE , Holzer M , Pasterk L , Heinemann A , Marsche G
Ref : Biochimica & Biophysica Acta , 1861 :630 , 2016
Abstract : High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk.
ESTHER : Trieb_2016_Biochim.Biophys.Acta_1861_630
PubMedSearch : Trieb_2016_Biochim.Biophys.Acta_1861_630
PubMedID: 27106140

Title : Lp-PLA2, plaque inflammation and lesion development vary fundamentally between different vascular sites -
Author(s) : Marsche G
Ref : J Am Heart Assoc , 4 : , 2015
PubMedID: 25672370

Title : alpha\/beta Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal\/Lysosomal Lipid Bis(monoacylglycero)phosphate - Pribasnig_2015_J.Biol.Chem_290_29869
Author(s) : Pribasnig MA , Mrak I , Grabner GF , Taschler U , Knittelfelder O , Scherz B , Eichmann TO , Heier C , Grumet L , Kowaliuk J , Romauch M , Holler S , Anderl F , Wolinski H , Lass A , Breinbauer R , Marsche G , Brown JM , Zimmermann R
Ref : Journal of Biological Chemistry , 290 :29869 , 2015
Abstract : alpha/beta Hydrolase domain-containing 6 (ABHD6) can act as monoacylglycerol hydrolase and is believed to play a role in endocannabinoid signaling as well as in the pathogenesis of obesity and liver steatosis. However, the mechanistic link between gene function and disease is incompletely understood. Here we aimed to further characterize the role of ABHD6 in lipid metabolism. We show that mouse and human ABHD6 degrade bis(monoacylglycero)phosphate (BMP) with high specific activity. BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes/lysosomes, where it plays a key role in the formation of intraluminal vesicles and in lipid sorting. Up to now, little has been known about the catabolism of this lipid. Our data demonstrate that ABHD6 is responsible for approximately 90% of the BMP hydrolase activity detected in the liver and that knockdown of ABHD6 increases hepatic BMP levels. Tissue fractionation and live-cell imaging experiments revealed that ABHD6 co-localizes with late endosomes/lysosomes. The enzyme is active at cytosolic pH and lacks acid hydrolase activity, implying that it degrades BMP exported from acidic organelles or de novo-formed BMP. In conclusion, our data suggest that ABHD6 controls BMP catabolism and is therefore part of the late endosomal/lysosomal lipid-sorting machinery.
ESTHER : Pribasnig_2015_J.Biol.Chem_290_29869
PubMedSearch : Pribasnig_2015_J.Biol.Chem_290_29869
PubMedID: 26491015
Gene_locus related to this paper: human-ABHD6

Title : Distinct composition of human fetal HDL attenuates its anti-oxidative capacity - Sreckovic_2013_Biochim.Biophys.Acta_1831_737
Author(s) : Sreckovic I , Birner-Gruenberger R , Obrist B , Stojakovic T , Scharnagl H , Holzer M , Scholler M , Philipose S , Marsche G , Lang U , Desoye G , Wadsack C
Ref : Biochimica & Biophysica Acta , 1831 :737 , 2013
Abstract : In human high-density lipoprotein (HDL) represents the major cholesterol carrying lipoprotein class in cord blood, while cholesterol is mainly carried by low-density lipoprotein in maternal serum. Additionally, to carrying cholesterol, HDL also associates with a range of proteins as cargo. We tested the hypothesis that fetal HDL carries proteins qualitatively and quantitatively different from maternal HDL. These differences then contribute to distinct HDL functionality in both circulations. Shotgun proteomics and biochemical analyses were used to assess composition/function of fetal and maternal HDL isolated from uncomplicated human pregnancies at term of gestation. The pattern of analyzed proteins that were statistically elevated in fetal HDL (apoE, proteins involved in coagulation, transport processes) suggests a particle characteristic for the light HDL2 sub-fraction. In contrast, proteins that were enriched in maternal HDL (apoL, apoF, PON1, apoD, apoCs) have been described almost exclusively in the dense HDL3 fraction and relevant to its anti-oxidative function and role in innate immunity. Strikingly, PON1 mass and activity were 5-fold lower (p<0.01) in the fetus, which was accompanied by attenuation of anti-oxidant capacity of fetal HDL. Despite almost equal quantity of CETP in maternal and fetal HDL, its enzymatic activity was 55% lower (p<0.001) in the fetal circulation, whereas LCAT activity was not altered. These findings indicate that maternally derived HDL differs from fetal HDL with respect to its proteome, size and function. Absence of apoA-1, apoL and PON1 on fetal HDL is associated with decreased anti-oxidative properties together with deficiency in innate immunity collectively indicating distinct HDLs in fetuses.
ESTHER : Sreckovic_2013_Biochim.Biophys.Acta_1831_737
PubMedSearch : Sreckovic_2013_Biochim.Biophys.Acta_1831_737
PubMedID: 23321267

Title : The prostaglandin E2 receptor EP4 is expressed by human platelets and potently inhibits platelet aggregation and thrombus formation - Philipose_2010_Arterioscler.Thromb.Vasc.Biol_30_2416
Author(s) : Philipose S , Konya V , Sreckovic I , Marsche G , Lippe IT , Peskar BA , Heinemann A , Schuligoi R
Ref : Arterioscler Thromb Vasc Biol , 30 :2416 , 2010
Abstract : OBJECTIVE: Low concentrations of prostaglandin (PG) E(2) enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE(2) are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE(2) has been suggested to involve EP3 receptors. Here we analyzed the receptor usage relating to the inhibitory effect of PGE(2). METHODS AND
RESULTS: Using flow cytometry, we found that human platelets expressed EP4 receptor protein. A selective EP4 agonist (ONO AE1-329) potently inhibited the platelet aggregation as induced by ADP or collagen. This effect could be completely reversed by an EP4 antagonist, but not by PGI(2), PGD(2), and thromboxane receptor antagonists or cyclooxygenase inhibition. Moreover, an EP4 antagonist enhanced the PGE(2)-induced stimulation of platelet aggregation, indicating a physiological antiaggregatory activity of EP4 receptors. The inhibitory effect of the EP4 agonist was accompanied by attenuated Ca(2+) flux, inhibition of glycoprotein IIb/IIIa, and downregulation of P-selectin. Most importantly, adhesion of platelets to fibrinogen under flow and in vitro thrombus formation were effectively prevented by the EP4 agonist. In this respect, the EP4 agonist synergized with acetylsalicylic acid.
CONCLUSIONS: These results are suggestive of EP4 receptor activation as a novel antithrombotic strategy.
ESTHER : Philipose_2010_Arterioscler.Thromb.Vasc.Biol_30_2416
PubMedSearch : Philipose_2010_Arterioscler.Thromb.Vasc.Biol_30_2416
PubMedID: 21071691