Feldkirch, Austria
Feldkirch, Austria

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Fraunberger P.,Medical Central Laboratories | Fraunberger P.,Ludwig Maximilians University of Munich | Grone E.,German Cancer Research Center | Grone H.-J.,German Cancer Research Center | And 2 more authors.
Journal of Inflammation (United Kingdom) | Year: 2017

Background: Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. Methods: Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in Guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. Results: Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. Conclusion: In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our Guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined. © 2017 The Author(s).


Leiherer A.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Leiherer A.,University of Liechtenstein | Leiherer A.,Medical Central Laboratories | Geiger K.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | And 7 more authors.
Molecular and Cellular Endocrinology | Year: 2014

To elucidate the complex impact of hypoxia on adipose tissue, resulting in biased metabolism, insulin resistance and finally diabetes we used mature adipocytes derived from a Simpson-Golabi-Behmel syndrome patient for microarray analysis. We found a significantly increased transcription rate of genes involved in glycolysis and a striking association between the pattern of upregulated genes and disease biomarkers for diabetes mellitus and insulin resistance. Although their upregulation turned out to be HIF-1α-dependent, we identified further transcription factors mainly AP-1 components to play also an important role in hypoxia response. Analyzing the regulatory network of mentioned transcription factors and glycolysis targets we revealed a clear hint for directing glycolysis to glutathione and glycogen synthesis. This metabolic switch in adipocytes enables the cell to prevent oxidative damage in the short term but might induce lipogenesis and establish systemic metabolic disorders in the long run. © 2013 The Authors.


Geiger K.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Geiger K.,University of Liechtenstein | Muendlein A.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Muendlein A.,University of Liechtenstein | And 11 more authors.
Hormone and Metabolic Research | Year: 2011

Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O2, 94% N, and 5% CO2). In addition, hypoxic conditions were mimicked by using CoCl2. The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1. © Georg Thieme Verlag KG Stuttgart - New York.


Geiger K.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Geiger K.,University of Liechtenstein | Leiherer A.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Leiherer A.,University of Liechtenstein | And 16 more authors.
PLoS ONE | Year: 2011

Hypoxia in adipose tissue is suggested to be involved in the development of a chronic mild inflammation, which in obesity can further lead to insulin resistance. The effect of hypoxia on gene expression in adipocytes appears to play a central role in this inflammatory response observed in obesity. However, the global impact of hypoxia on transcriptional changes in human adipocytes is unclear. Therefore, we compared gene expression profiles of human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes under normoxic or hypoxic conditions to detect hypoxia-responsive genes in adipocytes by using whole human genome microarrays. Microarray analysis showed more than 500 significantly differentially regulated mRNAs after incubation of the cells under low oxygen levels. To gain further insight into the biological processes, hypoxia-regulated genes after 16 hours of hypoxia were classified according to their function. We identified an enrichment of genes involved in important biological processes such as glycolysis, response to hypoxia, regulation of cellular component movement, response to nutrient levels, regulation of cell migration, and transcription regulator activity. Real-time PCR confirmed eight genes to be consistently upregulated in response to 3, 6 and 16 hours of hypoxia. For adipocytes the hypoxia-induced regulation of these genes is shown here for the first time. Moreover in six of these eight genes we identified HIF response elements in the proximal promoters, specific for the HIF transcription factor family members HIF1A and HIF2A. In the present study, we demonstrated that hypoxia has an extensive effect on gene expression of SGBS adipocytes. In addition, the identified hypoxia-regulated genes are likely involved in the regulation of obesity, the incidence of type 2 diabetes, and the metabolic syndrome. © 2011 Geiger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Rein P.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Rein P.,Academic Teaching Hospital Feldkirch | Rein P.,University of Liechtenstein | Saely C.H.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | And 10 more authors.
Atherosclerosis | Year: 2015

People with chronic kidney disease frequently experience cardiovascular events. This study sought to investigate whether the presence of albuminuria displays a vascular risk equivalent to that in patients with prior myocardial infarction. Methods: Albuminuria was defined as a urinary albumin to creatinine ratio of 30μg/mg or greater in 852 consecutive patients undergoing coronary angiography. Prospectively, we recorded vascular events over 3.2±1.2 years. Results: From our patients, 513 (60.2%) had neither albuminuria nor a history of MI, 126 (14.8%) had albuminuria without prior MI, 137 (16.1%) did not have albuminuria but had a history of MI, and 76 (8.9%) had both, albuminuria and prior MI. Compared with the incidence of the composite endpoint among normoalbuminuric patients with no prior MI (11.9%), event rates nearly doubled both in patients with albuminuria without prior MI (24.6%; p=0.003) and in normoalbuminuric patients with a history of prior MI (21.2%; p=0.004) and were highest in patients with both, albuminuria and prior MI (36.8%; p<0.001). Importantly, event rates were not significantly different between patients with albuminuria and no prior history of MI and those with normoalbuminuria but prior MI (p=0.972). Moreover, the event rate in patients with both, albuminuria and history of MI, was significantly higher (p<0.05) than in the two groups exhibiting only one of the two conditions. Conclusion: This is the first study demonstrating that albuminuria is a CAD risk equivalent. Thus, cardiovascular risk factors in albuminuric patients should be treated as aggressively as in patients with prior MI. © 2015 Elsevier Ireland Ltd.


Leiherer A.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | Leiherer A.,University of Liechtenstein | Leiherer A.,Medical Central Laboratories | Mundlein A.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | And 5 more authors.
Vascular Pharmacology | Year: 2013

Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too.In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo. © 2012 Elsevier Inc.


PubMed | Drexel University, Medical Central Laboratories and University of Liechtenstein
Type: Comparative Study | Journal: Atherosclerosis | Year: 2015

People with chronic kidney disease frequently experience cardiovascular events. This study sought to investigate whether the presence of albuminuria displays a vascular risk equivalent to that in patients with prior myocardial infarction.Albuminuria was defined as a urinary albumin to creatinine ratio of 30 g/mg or greater in 852 consecutive patients undergoing coronary angiography. Prospectively, we recorded vascular events over 3.21.2 years.From our patients, 513 (60.2%) had neither albuminuria nor a history of MI, 126 (14.8%) had albuminuria without prior MI, 137 (16.1%) did not have albuminuria but had a history of MI, and 76 (8.9%) had both, albuminuria and prior MI. Compared with the incidence of the composite endpoint among normoalbuminuric patients with no prior MI (11.9%), event rates nearly doubled both in patients with albuminuria without prior MI (24.6%; p=0.003) and in normoalbuminuric patients with a history of prior MI (21.2%; p=0.004) and were highest in patients with both, albuminuria and prior MI (36.8%; p<0.001). Importantly, event rates were not significantly different between patients with albuminuria and no prior history of MI and those with normoalbuminuria but prior MI (p=0.972). Moreover, the event rate in patients with both, albuminuria and history of MI, was significantly higher (p<0.05) than in the two groups exhibiting only one of the two conditions.This is the first study demonstrating that albuminuria is a CAD risk equivalent. Thus, cardiovascular risk factors in albuminuric patients should be treated as aggressively as in patients with prior MI.


PubMed | Vorarlberg Institute for Vascular Investigation and Treatment VIVIT, Drexel University, Medical Central Laboratories, Academic Teaching Hospital Feldkirch and University of Liechtenstein
Type: Journal Article | Journal: Atherosclerosis | Year: 2015

Niemann-Pick C1-like 1 (NPC1L1) is involved in dietary cholesterol absorption and is the direct molecular target of the LDL-lowering drug ezetimibe. Recently, genetic variants in NPC1L1 have been associated with the incidence of cardiovascular events, but it remains unclear if the impact of NPC1L1 on cardiovascular risk is dependent on its role in cholesterol absorption. Furthermore, no direct association of genetic variants in NPC1L1 with coronary atherosclerosis has been established.To further address these issues, we determined the impact of 34 single nucleotide polymorphisms (SNPs) at the NPC1L1 gene locus on the presence of coronary atherosclerosis and prospectively on future cardiovascular events in a cohort of 984 angiographied Caucasian patients.Out of investigated SNPs, 24 variants were significantly associated with future cardiovascular events. The highest impact was observed for rs55837134 (sex-and age adjusted additive HR = 1.67 [1.28-2.18]; p = 1.3 e-4). Regression analysis conditioned on rs55837134 showed that significant associations between remaining SNPs at the NPC1L1 locus and vascular events did not persist suggesting their dependence on rs55837134. Its significant association remained almost unchanged after further adjustment for total cholesterol, LDL cholesterol, and other cardiovascular risk factors (additive HR = 1.67 [1.28-2.18]; p = 1.7 e-4). In addition, no significant association of investigated NPC1L1 variants with coronary atherosclerosis could be observed, at least after false discovery rate correction.Genetic variants of NPC1L1, particularly rs55837134, show a predictive impact on cardiovascular events. Further studies to determine the molecular consequences of common genetic variants in NPC1L1 are needed.


PubMed | Vorarlberg Institute for Vascular Investigation and Treatment VIVIT, Drexel University, Medical Central Laboratories, Academic Teaching Hospital Feldkirch and University of Liechtenstein
Type: Journal Article | Journal: Atherosclerosis | Year: 2014

Angiopoietin-like protein 4 (ANGPTL4) has been associated with cardiometabolic disorders including dyslipidemia and atherosclerosis in animal studies; in humans, however, its impact on metabolic traits and cardiovascular risk remains unclear.We examined the association of plasma ANGPTL4 levels with the metabolic syndrome (harmonized consensus definition), with angiographically determined coronary artery disease (CAD), and with the risk of future cardiovascular events in a cohort of 490 patients undergoing coronary angiography for the evaluation of stable CAD. In addition, we investigated the influence of the tagging single nucleotide polymorphisms (SNPs) rs4076317, rs2278236, rs1044250, and rs11672433 as well as variant rs116843064 (E40K) of the ANGPTL4 gene on cardiovascular risk in a larger sample of 983 angiographied coronary patients including the above mentioned 490 subjects.Plasma ANGPTL4 was significantly higher in patients with the metabolic syndrome than in subjects without the metabolic syndrome (26.0 19.4 ng/ml vs. 22.2 19.7 ng/ml; p = 0.008). No significant association was found between ANGPTL4 and angiographically characterized coronary atherosclerosis. Prospectively, however, plasma ANGPTL4 significantly predicted future cardiovascular events both univariately (HR1.45 [1.16-1.82], p = 0.001) and after adjustment for standard cardiovascular risk factors (1.26 [1.01-1.58]; p = 0.045). Concordantly, rs4076317, rs2278236, and rs1044250 significantly affected the risk of future cardiovascular events (adjusted HRs 0.70 [0.54-0.90]; p = 0.005, 0.76 [0.61-0.94]; p = 0.012, and 1.30 [1.03-1.62]; p = 0.025, respectively).We conclude that plasma ANGPTL4 levels as well as ANGPTL4 variants significantly predict cardiovascular events independently of conventional cardiovascular risk factors.


Biller K.,Medical Central Laboratories | Fae P.,Academic Teaching Hospital | Germann R.,Academic Teaching Hospital | Drexel H.,Vorarlberg Institute for Vascular Investigation and Treatment VIVIT | And 2 more authors.
Shock | Year: 2014

Serum cholesterol procalcitonin (PCT) and C-reactive protein (CRP) levels were measured consecutively in 76 critically ill patients at admission to the intensive care unit. The presence of infection was defined according to the CDC (Centers for Disease Control and Prevention) criteria; in-house mortality, underlying diseases, and severity of sepsis were monitored. Nonsurvivors had significantly lower cholesterol levels compared with survivors (69 mg/dL [range, 37-88 mg/dL] vs. 96 mg/dL [range, 71-132 mg/dL], P = 0.006) whereas no significant differences were noted for serum PCT and CRP levels. In a cohort of patients with cholesterol levels of 50 mg/dL or less, 82% did not survive as compared with patients with cholesterol levels of 100 mg/dL or greater (mortality, 21%). In a control group without infection, no difference of cholesterol, PCT, or CRP was found between survivors and nonsurvivors. Our data show that low cholesterol levels in patients with infectious disease have a prognostic value and may be useful markers to identify high-risk patients already at admission. Copyright © 2014 by the Shock Society.

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