Publications by authors named "Hubert Scharnagl"

181 Publications

The effects of long-term moderate exercise and Western-type diet on oxidative/nitrosative stress, serum lipids and cytokines in female Sprague Dawley rats.

Eur J Nutr 2021 Jul 28. Epub 2021 Jul 28.

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 15/1 Auenbruggerplatz, 8036, Graz, Austria.

Purpose: Regular exercise reduces obesity and the risk of cardiovascular disease. However, health-promoting benefits of physical activity are commonly associated with increased inflammation and oxidative stress. Here, we tested whether constant moderate exercise is able to prevent or attenuate the oxidative/nitrosative stress, inflammation, and serum lipids in lean and obese rats.

Methods: Four-month-old female Sprague Dawley rats received standard or a high-fat diet. Animals were subjected to a physical activity protocol, consisting of 30 min forced treadmill exercise for 5 consecutive days per week during 10 months. Baseline and sedentary (non-exercised) rats were used as controls. Lipids, oxidized low-density lipoprotein cholesterol, nitric oxide metabolites, and pro- and anti-inflammatory markers were measured in blood collected upon euthanasia.

Results: At variance to young baseline control rats, 14-month-old animals fed normal diet had increased plasma lipid levels, including total cholesterol and triglycerides, which were further elevated in rats that consumed a high-fat diet. While treadmill exercise did not lower the amount of serum lipids in standard diet group, forced physical activity reduced non-high-density lipoprotein cholesterol in response to high-fat diet feeding. Exercised rats fed standard diet or high-fat diet had lower abundancy of nitric oxide metabolites, which coincided with increased levels of oxidized low-density lipoprotein cholesterol. Accordingly, the amount of nitric oxide metabolites correlated inversely with oxidized low-density lipoprotein cholesterol and homo-arginine. Exercise significantly reduced inflammatory cytokines in high-fat diet fed rats only.

Conclusion: Our study suggests that regular exercise alters the equilibrium between oxidative and anti-oxidative compounds and reduces pro-inflammatory cytokines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00394-021-02639-4DOI Listing
July 2021

24-NorUrsodeoxycholic acid reshapes immunometabolism in CD8 T-cells and alleviates hepatic inflammation.

J Hepatol 2021 Jul 6. Epub 2021 Jul 6.

Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Background & Aims: 24-NorUrsodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC) where dysregulated T-cells including CD8 T-cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8 T-cell function thus contributing to its therapeutic efficacy.

Methods: NorUDCA's immunomodulatory effects were first studied in Mdr2 mice as cholestatic model of PSC. To dissect NorUDCA's immunomodulatory effects on CD8 T-cell function from its anti-cholestatic actions, the mechanisms were also explored in a non-cholestatic model of hepatic injury induced by excessive CD8 T-cell immune response upon acute non-cytolytic lymphocytic-choriomeningitis-virus (LCMV) infection. Studies included molecular and biochemical approaches, flow cytometry and metabolic assays in murine CD8 T-cells in vitro. Mass spectrometry (MS) was used to identify potential CD8 T-cell targets modulated by NorUDCA. NorUDCA's signaling effects observed in murine cells were validated in circulating T-cells from PSC patients.

Results: NorUDCA demonstrated immunomodulatory effects by reducing hepatic innate and adaptive immune cells, including CD8 T-cells in Mdr2 model. In the non-cholestatic model of CD8 T cell-driven immunopathology induced by acute LCMV infection, NorUDCA ameliorated hepatic injury and systemic inflammation. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8 T-cells affecting lymphoblastogenesis, expansion, glycolysis and mTORC1 signaling. MS identified that NorUDCA regulates CD8 T-cells via targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating PSC CD8 T-cells.

Conclusions: NorUDCA possesses direct modulatory potency on CD8 T-cells and attenuates excessive CD8 T cell-driven hepatic immunopathology. These findings are relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

Lay Summary: Elucidating the mechanisms of 24-NorUrsodeoxycholic acid (NorUDCA) as novel therapeutic approach to immune-mediated liver diseases, such as primary sclerosing cholangitis (PSC), is of considerable clinical interest. This study explored the immunomodulatory properties of NorUDCA on CD8 T-cells whose dysregulation contribute to hepatobiliary immunopathology in PSC. Using comprehensive in vivo and in vitro experimental approaches, we uncovered a yet-unrecognized immunometabolic regulatory property of NorUDCA adding to its previously established anti-cholestatic effects, explaining mechanistic aspects of its therapeutic potential in immune-mediated liver diseases including PSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.06.036DOI Listing
July 2021

Effects of empagliflozin on lipoprotein subfractions in patients with type 2 diabetes: data from a randomized, placebo-controlled study.

Atherosclerosis 2021 Jun 25;330:8-13. Epub 2021 Jun 25.

Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.

Background And Aims: Sodium-glucose cotransporter-2 inhibitors, glucose-lowering drugs that increase urinary glucose excretion, have been shown to reduce CV events in patients with type 2 diabetes (T2D), despite the fact that these agents increase blood levels of the proatherogenic low density lipoprotein cholesterol (LDL-C). It has been hypothesized that hemoconcentration due to osmotic diuresis, effects on calculated LDL particle size, or a modulation of lipoprotein subfractions may play a role in this context but to date the underlying mechanisms remain largely unexplored. Therefore, the present study examined effects of empagliflozin on LDL-C and lipoprotein subfractions including calculated LDL particle size and composition.

Methods: In this placebo-controlled, randomized, double blind study, patients with T2D were randomized to empagliflozin 10 mg (n = 20) or placebo (n = 22). Composition of lipoprotein subfractions was assessed before and after 3 months of treatment. Lipoproteins were separated using a combined ultracentrifugation-precipitation method (β-quantification).

Results: Empagliflozin increased LDL-C after 3 months of treatment (from baseline: 103 ± 36 mg/dL to 112 ± 47 mg/dL; p < 0.001) while no difference was recorded after day 1 or day 3 of treatment. The increase of LDL-C was paralleled by an increase of total cholesterol (baseline: 169 ± 41 mg/dL, 3 months: 185 ± 48 mg/dL; p = 0.001). Analyses of lipoprotein subfractions revealed LDL phospholipids and LDL apolipoprotein B to be increased by empagliflozin after 3 months of treatment while calculated LDL particle size was not affected. In addition empagliflozin increased free fatty acid concentrations.

Conclusions: Empagliflozin treatment of patients with T2D increased LDL-C and LDL apolipoprotein B levels but had no effect on calculated LDL particle size.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2021.06.915DOI Listing
June 2021

Serum markers of fibrosis, cardiovascular and all-cause mortality in hemodialysis patients: the AURORA trial.

Clin Res Cardiol 2021 Jun 25. Epub 2021 Jun 25.

Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm U1116, CHRU Nancy; F-CRIN INI-CRCT, Nancy, France.

Background: Biomarkers of fibrosis are associated with outcome in several cardiovascular diseases. However, their relevance to chronic kidney disease and dialysis is uncertain, as it remains unclear how the kidneys and the dialysis procedure itself affect their elimination and degradation. We aimed to investigate the relationship of the blood levels of two markers associated with fibrosis: procollagen type I C-terminal pro-peptide (PICP) and galectin-3 (Gal-3) with mortality in dialysis patients.

Methods: Procollagen type I C-terminal pro-peptide and galectin-3 were measured at baseline in 2773 patients enrolled in the AURORA trial, investigating the effect of rosuvastatin on cardiovascular outcomes, in patients on hemodialysis, and their interaction with CV death or all-cause mortality using survival models. The added prognostic value of these biomarkers was assessed by the net reclassification improvement (NRI).

Results: The median follow-up period was 3.8 years. Blood concentrations of PICP and Gal-3 were significantly associated with CV death [adjusted HR per 1 SD = 1.11 (1.02-1.20) and SD = 1.20 (1.10-1.31), respectively] and all-cause mortality (all adjusted p < 0.001). PICP and Gal-3 had a synergistic effect with regard to CV death and all-cause mortality (interaction p = 0.04 and 0.01, respectively). Adding PICP, Gal-3 and their interaction on top of clinical and biological covariates, resulted in significantly improved prognostic accuracy NRI = 0.080 (0.019-0.143) for CV death.

Conclusion: In dialysis patients, concomitant increase in PICP and Gal-3 concentrations are associated with higher rates of CV death. These results suggest that concomitantly raised PICP and Gal-3 may reflect an activated fibrogenesis relevant to risk stratification in dialysis, raising the hypothesis that anti-fibrotic therapy may be beneficial for cardiovascular protection in such patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-021-01898-9DOI Listing
June 2021

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis.

Am J Cardiol 2021 Aug 6;152:63-68. Epub 2021 Jun 6.

Kidney Research Institute, University of Washington, Seattle, Washington.

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2021.04.023DOI Listing
August 2021

Biological anti-psoriatic therapy profoundly affects high-density lipoprotein function.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Jul 13;1866(7):158943. Epub 2021 Apr 13.

Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria; BioTechMed Graz, Mozartgasse 12/II, 8010 Graz, Austria. Electronic address:

Psoriasis is a common chronic inflammatory skin disease linked to increased cardiovascular risk. Functional impairment of high-density lipoprotein (HDL) may contribute to excessive cardiovascular mortality in psoriasis patients. Anti-cytokine therapies with biologics have been efficiently used for the management of psoriasis, however little data is available on the effects of biologic anti-psoriatic therapies on the composition and functionality of HDL. Blood samples were taken from 17 healthy volunteers and from 27 real-world psoriasis patients at baseline (no therapy with biologics) and after short-term (3 to 6 months) and intermediate-term (1 to 2 years) therapy. The biologics used included anti-interleukin (IL)-12/23p40 (ustekinumab), anti-IL17A (secukinumab) or anti-tumor necrosis factor-α (etanercept or adalimumab) antibodies. We observed that in psoriasis patients at baseline, metrics of HDL function including cholesterol efflux capacity of apolipoprotein B-depleted serum (p = 0.021), paraoxonase (p < 0.001) and lecithin-cholesterol acyltransferase (p < 0.001) activities were impaired, when compared to controls. Unexpectedly, we observed that short- and especially intermediate-term therapy with biologics markedly reduced HDL cholesterol efflux capacity (p < 0.001) and rendered HDL pro-inflammatory (p < 0.001), but increased paraoxonase (p = 0.009) and lecithin-cholesterol acyltransferase (p = 0.019) activities. All biologics caused similar changes in HDL composition, subclass distribution and cholesterol efflux capacity. Our results provide evidence that anti-psoriatic therapy with biologic agents is associated with changes in HDL functionality, particle composition and subclass distribution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2021.158943DOI Listing
July 2021

Reply to: "Prognostic value of HDL-related biomarkers in patients with HBV-related ACLF".

J Hepatol 2021 Jul 13;75(1):245-246. Epub 2021 Apr 13.

Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.04.002DOI Listing
July 2021

Obesity Affects HDL Metabolism, Composition and Subclass Distribution.

Biomedicines 2021 Feb 27;9(3). Epub 2021 Feb 27.

Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.

Background: Obesity increases the risk of coronary heart disease, partly due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol levels. Functional impairment of HDL may contribute to the increased cardiovascular mortality, but the effect of obesity on composition, structure, and function of HDL is not well understood Design and Methods: We determined HDL composition, HDL subclass distribution, parameters of HDL function, and activities of most important enzymes involved in lipoprotein remodeling, including lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) in relatively young normal weight ( = 26), overweight ( = 22), and obese ( = 20) women.

Results: Obesity (body mass index (BMI) ≥ 30) was associated with noticeable changes in LCAT and CETP activities and altered HDL composition, such as decreased apolipoprotein A-I, cholesterol, and phospholipid content, while pro-inflammatory HDL serum amyloid a content was increased. We observed a marked shift towards smaller HDL subclasses in obesity linked to lower anti-oxidative capacity of serum. LCAT activity, HDL subclass distribution, and HDL-cholesterol were associated with soluble leptin receptor, adiponectin, and liver enzyme activities. Of note, most of these alterations were only seen in obese women but not in overweight women.

Conclusions: Obesity markedly affects HDL metabolism, composition, and subclass distribution linked to changes in liver and adipose tissue. HDL dysfunction may contribute to increased cardiovascular risk in obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9030242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997277PMC
February 2021

Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice.

Int J Mol Sci 2021 Feb 20;22(4). Epub 2021 Feb 20.

Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria.

Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3-PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout () mice lacking both and ; mice were compared to after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of and resulted in weight gain on a chow diet; when challenged by HFD, mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. deficiency aggravates the effects of deletion on steatosis and inflammation in the liver under HFD challenge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22042126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924608PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 Apr;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Composite Measures of Physical Fitness to Discriminate Between Healthy Aging and Heart Failure: The COmPLETE Study.

Front Physiol 2020 15;11:596240. Epub 2020 Dec 15.

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United States.

Background: Aging and changing age demographics represent critical problems of our time. Physiological functions decline with age, often ending in a systemic process that contributes to numerous impairments and age-related diseases including heart failure (HF). We aimed to analyze whether differences in composite measures of physiological function [health distance (HD)], specifically physical fitness, between healthy individuals and patients with HF, can be observed.

Methods: The COmPLETE Project is a cross-sectional study of 526 healthy participants aged 20-91 years and 79 patients with stable HF. Fifty-nine biomarkers characterizing fitness (cardiovascular endurance, muscle strength, and neuromuscular coordination) and general health were assessed. We computed HDs as the Mahalanobis distance for vectors of biomarkers (all and domain-specific subsets) that quantified deviations of individuals' biomarker profiles from "optimums" in the "reference population" (healthy participants aged <40 years). We fitted linear regressions with HD outcomes and disease status (HF/Healthy) and relevant covariates as predictors and logistic regressions for the disease outcome and sex, age, and age as covariates in the base model and the same covariates plus combinations of one or two HDs.

Results: Nine out of 10 calculated HDs showed evidence for group differences between Healthy and HF ( ≤ 0.002) and most models presented a negative estimate of the interaction term age by group ( < 0.05 for eight HDs). The predictive performance of the base model for HF cases significantly increased by adding HD or HD [areas under the receiver operating characteristic (ROC) curve (AUCs) 0.63, 0.89, and 0.84, respectively]. HD alone reached an AUC of 0.88. Further, there is evidence that the combination of HDs and shows superior predictive power compared to single HDs.

Conclusion: HD composed of physical fitness biomarkers differed between healthy individuals and patients with HF, and differences between groups diminished with increasing age. HDs can successfully predict HF cases, and HD can significantly increase the predictive power beyond classic clinical biomarkers. Applications of HD could strengthen a comprehensive assessment of physical fitness and may present an optimal target for interventions to slow the decline of physical fitness with aging and, therefore, to increase health span.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.596240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770139PMC
December 2020

Cholesterol Efflux Capacity and Cardiovascular Disease: The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

Biomedicines 2020 Nov 21;8(11). Epub 2020 Nov 21.

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria.

(1) Background and Aims: Efforts to reduce coronary artery disease (CAD) by raising high-density lipoprotein (HDL) cholesterol (HDL-C) have not been uniformly successful. A more important factor than HDL-C may be cellular cholesterol efflux mediated by HDL, which has been shown to be associated with CAD. In this report, we analyzed the influence of cardiovascular biomarkers and risk factors on cholesterol efflux in a prospective observational study of patients referred to coronary angiography. (2) Methods: HDL-mediated efflux capacity was determined for 2468 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 9.9 years. Primary and secondary endpoints were cardiovascular and all-cause mortality, respectively. (3) Results: Cholesterol efflux strongly correlated with HDL-related markers including HDL cholesterol, HDL phospholipids, and apolipoproteins AI and AII, as well as HDL particle concentration, which was not seen for low density lipoprotein (LDL) markers including LDL cholesterol and apoB. Cholesterol efflux was associated negatively with C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), and serum amyloid A. Cardiovascular mortality was higher in patients in the lowest cholesterol efflux quartile. This association was weakened, but not fully abolished, after adjustment for HDL cholesterol. (4) Conclusions: We demonstrate that cholesterol efflux was associated with HDL-composition as well as inflammatory burden in patients referred for coronary angiography, and that this inversely predicts cardiovascular mortality independently of HDL cholesterol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8110524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700479PMC
November 2020

PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis.

EMBO Rep 2020 12 23;21(12):e50893. Epub 2020 Nov 23.

Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence-free survival in HCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.202050893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726793PMC
December 2020

Common APOC3 variants are associated with circulating ApoC-III and VLDL cholesterol but not with total apolipoprotein B and coronary artery disease.

Atherosclerosis 2020 10 5;311:84-90. Epub 2020 Sep 5.

Mannheimer Institute for Public Health, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.

Background And Aims: Very rare loss-of-function mutations in the apolipoprotein C3 (APOC3) gene have been associated with low circulating apoC-III, low triglycerides, and reduced cardiovascular risk. We aimed to analyze the impact of common APOC3 variants on key parameters of lipid metabolism and coronary artery disease in the largest sample so far.

Methods: Common variants in APOC3 were tested for associations with circulating apoC-III, lipids, and apolipoprotein B (apoB) in 3041 participants of the LUdwigshafen RIsk and Cardiovascular health study (LURIC). These variants were then tested for associations with coronary artery disease in a meta-analysis comprising up to 332,389 participants of the CARDIOGRAMplusC4D consortium and the UK Biobank.

Results: The mean (standard deviation) apoC-III concentration was 14.6 (5.1) mg/dl. Seven common variants in APOC3 (rs734104, rs4520, rs5142, rs5141, rs5130, rs5128, and rs4225) were associated with circulating apoC-III (all p < 0.05). The alleles that modestly raised apoC-III were also associated with markedly higher total triglycerides and very low density lipoprotein (VLDL) triglycerides and cholesterol (all p < 0.05), but not with low density lipoprotein (LDL) cholesterol and total apoB (all p > 0.05). These variants were not associated with coronary artery disease in the CARDIOGRAMplusC4D consortium and the UK Biobank (all p > 0.1).

Conclusions: Modest, genetically caused elevations of apoC-III are associated with a marked increase of triglyceride-rich lipoproteins but not with an increase of LDL cholesterol, total apoB, and coronary artery disease. Whether effective inhibition of apoC-III production with antisense oligomers will be instrumental to reduce cardiovascular risk remains to be demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2020.08.017DOI Listing
October 2020

Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity.

Sci Rep 2020 09 14;10(1):15001. Epub 2020 Sep 14.

Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria.

Recent observations strongly connect high-density lipoproteins (HDL) function and levels with coronary heart disease outcomes and risk for infections and sepsis. To date, our knowledge of factors determining this connection is still very limited. The immobility associated with prolonged bedrest is detrimental to health, affecting several systems, including the cardiovascular, pulmonary, gastrointestinal, musculoskeletal and urinary. Effects of prolonged bedrest on the composition and functional properties of HDL remain elusive. We evaluated metrics of HDL composition and function in healthy male volunteers participating in a randomized, crossover head-down bedrest study. We observed that HDL cholesterol efflux capacity was profoundly decreased during bedrest, mediated by a bedrest associated reduction in plasma levels of HDL-cholesterol and major apolipoproteins (apo) apoA-I and apoA-II. Paraoxonase activity, plasma anti-oxidative capacity and the activities of lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein were not affected. No change was observed in the content of HDL-associated serum amyloid A, a sensitive marker of inflammation. Resistive vibration exercise countermeasure during bedrest did not correct impaired cholesterol efflux capacity and only tended to increase arylesterase activity of HDL-associated paraoxonase. In conclusion, prolonged bedrest reduces plasma HDL levels linked to markedly suppressed HDL cholesterol efflux capacity. Resistive vibration exercise during bedrest did not correct HDL levels and impaired cholesterol efflux capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71921-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490699PMC
September 2020

Reduced LDL-Cholesterol and Reduced Total Cholesterol as Potential Indicators of Early Cancer in Male Treatment-Naïve Cancer Patients With Pre-cachexia and Cachexia.

Front Oncol 2020 4;10:1262. Epub 2020 Aug 4.

Clinical Department of Internal Medicine II, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.

Cancer cachexia is characterized by the impairment of glucose and lipid homeostasis, the acceleration of processes promoting the mobilization of energy-rich compounds (e.g., insulin resistance, gluconeogenesis, and lipolysis) and the simultaneous activation of highly energy-demanding processes (e.g., systemic inflammation and activation of brown adipose tissue). We hypothesized that these processes might themselves change during cancer cachexia progression, such that plasma levels of glucose and lipids might be used to distinguish between the non-malignant state, pre-cachexia and cachexia. We performed an initial cross-sectional study including 60 treatment naïve cancer patients (38 with cancer cachexia and 22 with cancer pre-cachexia) and 61 patients without malignancy (21 with metabolic syndrome and 40 controls). Differences in lipids (total cholesterol, LDL and HDL cholesterol) and plasma fasting glucose were analyzed across various group configurations, with adjustments to age and antidiabetic or lipid-lowering drugs. Our study showed that levels of LDL cholesterol and total cholesterol might indicate cachexia stages irrespective of the presence of metabolic syndrome or lipid-lowering medication. High levels of plasma glucose were only seen in cachectic cancer patients on antidiabetics. These observations indicate that markers of metabolic dysregulation associated with cachexia progression might be exploited for early detection of malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.01262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417624PMC
August 2020

Performance of early pregnancy HbA for predicting gestational diabetes mellitus and adverse pregnancy outcomes in obese European women.

Diabetes Res Clin Pract 2020 Oct 21;168:108378. Epub 2020 Aug 21.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; Institute of Sport Science, University of Graz, Graz, Austria.

Aims: To investigate the performance of early pregnancy HbA for predicting gestational diabetes mellitus (GDM) and adverse pregnancy outcomes in obese women.

Methods: Post hoc analysis using data from the Vitamin D And Lifestyle Intervention for GDM prevention trials conducted across 9 European countries (2012-2014). Pregnant women (BMI ≥ 29 kg/m) underwent a baseline HbA and oral glucose tolerance tests at < 20 weeks, 24-28 weeks, and 35-37 weeks. Women with GDM were referred for treatment.

Results: Among the 869 women tested, the prevalence of GDM was 25.9% before 20 weeks, with a further 8.6% at 24-28 weeks. The areas under the curves for HbA at the two time points were 0.55 (0.50-0.59) and 0.54 (0.47-0.61), respectively. An early HbA ≥ 5.7% (39 mmol/mol) (N = 111) showed low sensitivity (18.2%) with 89.1% specificity for GDM before 20 weeks, at 24-28 weeks (sensitivity of 8.0% and specificity of 88.6% after excluding early GDM), and throughout gestation (sensitivity of 15.9% and specificity of 89.4%). The ≥ 5.7% (39 mmol/mol) threshold was significantly associated with concurrent GDM before 20 weeks (adjusted OR (aOR) 2.77(1.39-5.51)) and throughout gestation (aOR 1.72 (1.02-2.89)), but not adverse pregnancy outcomes.

Conclusions: Early pregnancy HbA is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2020.108378DOI Listing
October 2020

NT-proBNP for risk prediction of cardiovascular events and all-cause mortality: The getABI-study.

Int J Cardiol Heart Vasc 2020 Aug 5;29:100553. Epub 2020 Jun 5.

Cardiovascular Center, St. Josef Hospital Bochum, Ruhr-University Bochum, Germany.

Background: Beside their role in the diagnosis of heart failure in symptomatic patients with dyspnea, natriuretic peptides have been suggested to improve risk prediction of cardiac events and mortality in asymptomatic cohorts. We aimed to evaluate the prognostic value of NT-proBNP for cardiovascular and all-cause mortality above traditional risk factors in a prospective cohort study of unselected elderly patients in a representative primary care setting.

Methods: We followed 6382 patients of the getABI-study for 7 years. Associations of NT-proBNP levels (≤125; 125-300; >300pg/ml for all) with all-cause and cardiovascular mortality were assessed using cox regression analysis.

Results: The incidence of all-cause and cardiovascular mortality was higher in subjects with higher levels of NT-proBNP (all-cause mortality/cardiovascular mortality: 35.4%/6% for NT-proBNP > 300 pg/ml; 16.2%/40% for NT-proBNP 125-300 pg/ml vs. 11.4%/4% for NT-proBNP ≤ 125 pg/ml. Participants with a NT-proBNP levels > 300pg/ml had increased incidence of hard endpoint (hazard ratio (HR) (95% confidence interval (CI)): 3.62 (3.15-4.17) for all-cause mortality, and 6.38 (4.84-8.41) for cardiovascular mortality). These associations remained after adjustment for traditional risk factors and cardiac medications and diseases (HR = 2.64 (2.26-3.08) for all-cause mortality, and HR = 3.93 (2.90-5.32) for cardiovascular mortality).

Conclusion: Our results show strong associations of higher NT-proBNP levels with cardiovascular and all-cause mortality in an unselected, large population of elderly patients in the primary care setting independent of traditional risk factors indicating that NT-proBNP can help identifying subjects at high risk for cardiac events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2020.100553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280763PMC
August 2020

Cardiac involvement in a cross-sectional cohort of myotonic dystrophies and other skeletal myopathies.

ESC Heart Fail 2020 08 31;7(4):1900-1908. Epub 2020 May 31.

Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Aims: Cardiac involvement in myopathies that primarily affect the skeletal muscle is variable and may be subtle, necessitating sensitive diagnostic approaches. Here, we describe the prevalence of cardiac abnormalities in a cohort of patients with skeletal muscle disease presenting at a tertiary care neuromuscular centre.

Methods And Results: We systematically investigated patients with skeletal myopathies and comprehensively analysed their cardiac phenotype including 24 h electrocardiogram, echocardiography with strain analyses, contrast-enhanced cardiac magnetic resonance imaging, and, if at increased risk of coronary artery disease, computed tomography coronary angiography. We prospectively screened 91 patients with diverse skeletal myopathies and enrolled 73 patients. The most pronounced cardiac involvement was present in patients with dystrophic myopathies (cardiac abnormalities in 59% of patients). We analysed myotonic dystrophies (n = 29) in more detail and found prolonged QRS (99.4 ± 15.6 vs. 91.5 ± 10.3 ms; P = 0.027) and QTc times (441.1 ± 28.1 vs. 413.0 ± 23.3 ms; P < 0.001) and increased left atrial size (27.28 ± 3.9 vs. 25.0 ± 3.2 mm/m ; P = 0.021) when compared with healthy controls. Left ventricular systolic function was reduced (ejection fraction < 55%) in 31% of myotonic dystrophies, while only 4% had an ejection fraction < 50%. Apical peak systolic longitudinal strain was slightly reduced (P = 0.023).

Conclusions: Screening for cardiac involvement in the skeletal muscle disease seems prudent particularly in patients with dystrophic myopathies. In the subset of myotonic dystrophy patients, QRS and QTc times as well as myocardial strain may be useful parameters. Their potential for predicting cardiac adverse events needs further evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.12763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373928PMC
August 2020

Apolipoprotein CIII predicts cardiovascular events in patients with coronary artery disease: a prospective observational study.

Lipids Health Dis 2020 May 30;19(1):116. Epub 2020 May 30.

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstraße 20, 04103, Leipzig, Germany.

Background: Apolipoprotein CIII (apoCIII) is associated with triglyceride-rich lipoprotein metabolism and has emerged as independent marker for risk of cardiovascular disease. The objective was to test whether apoCIII is regulated postprandially and whether apoCIII concentrations in native and chylomicron-free serum predict future cardiovascular events in patients with stable coronary artery disease (CAD).

Methods: ApoCIII concentrations were measured in native and chylomicron-free serum in the fasting state and after a standardized oral fat load test in 195 patients with stable CAD. Clinical follow-up was 48 months. Chylomicron-free serum was prepared by ultracentrifugation (18,000 rpm, 3 h). The log-rank test and Cox regression analyses were used to investigate the association of apoCIII with recurrent cardiovascular events.

Results: Of the 195 patients included, 92 had a cardiovascular event, and 103 did not. 97% were treated with a statin. No significant changes in apoCIII concentration were observed after the oral fat load test. The apoCIII concentration was associated with event-free survival independent of conventional risk factors. This association reached statistical significance only for apoCIII concentration measured in chylomicron-free serum (hazard ratio [95% confidence interval] for apoCIII above the mean: postprandial: 1.67 (1.06-2.29), P = 0.028, fasting: 2.09 (1.32-3.32), P = 0.002), but not for apoCIII concentration measured in native serum (postprandial: 1.47 [0.89-2.43], P = 0.133, fasting: 1.56 [0.95-2.58], P = 0.081). The effects were independent of other risk factors.

Conclusions: ApoCIII concentrations in chylomicron-free serum are independently associated with event-free survival in patients with CAD both in fasting and postprandial state. This findings support considering apoCIII for risk assessment and attempting to test the hypothesis that lowering apoCIII reduces residual cardiovascular risk.

Take Home Message: Apolipoprotein CIII concentration measured in chylomicron-free serum predicts recurrent cardiovascular events in patients with stable coronary artery disease.

Trial Registration: The trial which included the participants of this study was registered at https://clinicaltrials.gov (NCT00628524) on March 5, 2008.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12944-020-01293-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260843PMC
May 2020

Author Correction: Cardiovascular risk algorithms in primary care: Results from the DETECT study.

Sci Rep 2020 Mar 31;10(1):5945. Epub 2020 Mar 31.

University of Heidelberg, Mannheim Medical Faculty, Department of Internal Medicine V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Mannheim, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59763-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105487PMC
March 2020

Absence of Bsep/Abcb11 attenuates MCD diet-induced hepatic steatosis but aggravates inflammation in mice.

Liver Int 2020 06 18;40(6):1366-1377. Epub 2020 Mar 18.

Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Bile acids (BAs) regulate hepatic lipid metabolism and inflammation. Bile salt export pump (BSEP) KO mice are metabolically preconditioned with a hydrophilic BA composition protecting them from cholestasis. We hypothesize that changes in hepatic BA profile and subsequent changes in BA signalling may critically determine the susceptibility to steatohepatitis.

Methods: Wild-type (WT) and BSEP KO mice were challenged with methionine choline-deficient (MCD) diet to induce steatohepatitis. Serum biochemistry, lipid profiling as well as intestinal lipid absorption were assessed. Markers of inflammation, fibrosis, lipid and BA metabolism were analysed. Hepatic and faecal BA profile as well as serum levels of the BA synthesis intermediate 7-hydroxy-4-cholesten-3-one (C4) were also investigated.

Results: Bile salt export pump KO MCD-fed mice developed less steatosis but more inflammation than WT mice. Intestinal neutral lipid levels were reduced in BSEP KO mice at baseline and under MCD conditions. Faecal non-esterified fatty acid concentrations at baseline and under MCD diet were markedly elevated in BSEP KO compared to WT mice. Serum liver enzymes and hepatic expression of inflammatory markers were increased in MCD-fed BSEP KO animals. PPARα protein levels were reduced in BSEP KO mice. Accordingly, PPARα downstream targets Fabp1 and Fatp5 were repressed, while NFκB subunits were increased in MCD-fed BSEP KO mice. Farnesoid X receptor (FXR) protein levels were reduced in MCD-fed BSEP KO vs WT mice. Hepatic BA profile revealed elevated levels of TβMCA, exerting FXR antagonistic action, while concentrations of TCA (FXR agonistic function) were reduced.

Conclusion: Presence of hydroxylated BAs result in increased faecal FA excretion and reduced hepatic lipid accumulation. This aggravates development of MCD diet-induced hepatitis potentially by decreasing FXR and PPARα signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317533PMC
June 2020

HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure.

J Hepatol 2020 07 14;73(1):113-120. Epub 2020 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Background & Aims: High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease.

Methods: HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality.

Results: Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77).

Conclusion: HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure.

Lay Summary: People who suffer from cirrhosis (scarring of the liver) have low levels of cholesterol carried by high-density lipoproteins (HDL-C). These alterations are connected to inflammation, which is a problem in severe liver disease. Herein, we show that reduced levels of HDL-C and apolipoprotein A-I (apoA-I, the main protein carried by HDL) are closely linked to the severity of liver failure, its complications and survival. Both HDL-C and apoA-I can be easily measured in clinical laboratories and are as good as currently used prognostic scores calculated from several laboratory values by complex formulas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.01.026DOI Listing
July 2020

E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration.

Dev Cell 2020 02 23;52(3):335-349.e7. Epub 2020 Jan 23.

Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

E2F transcription factors control the cytokinesis machinery and thereby ploidy in hepatocytes. If or how these proteins limit proliferation of polyploid cells with extra centrosomes remains unknown. Here, we show that the PIDDosome, a signaling platform essential for caspase-2-activation, limits hepatocyte ploidy and is instructed by the E2F network to control p53 in the developing as well as regenerating liver. Casp2 and Pidd1 act as direct transcriptional targets of E2F1 and its antagonists, E2F7 and E2F8, that together co-regulate PIDDosome expression during juvenile liver growth and regeneration. Of note, whereas hepatocyte aneuploidy correlates with the basal ploidy state, the degree of aneuploidy itself is not limited by PIDDosome-dependent p53 activation. Finally, we provide evidence that the same signaling network is engaged to control ploidy in the human liver after resection. Our study defines the PIDDosome as a primary target to manipulate hepatocyte ploidy and proliferation rates in the regenerating liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.devcel.2019.12.016DOI Listing
February 2020

Bile Acids in Patients with Uncontrolled Type 2 Diabetes Mellitus - The Effect of Two Days of Oatmeal Treatment.

Exp Clin Endocrinol Diabetes 2020 Sep 2;128(9):624-630. Epub 2020 Jan 2.

Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Beta-glucans are effective in binding bile acids (BA) thereby lowering cholesterol concentration. This might contribute to the beneficial effects of the consumption of β-glucan-rich foods like oatmeal on glucose homeostasis.

Objective: We measured BA serum concentrations in patients with uncontrolled type 2 diabetes (T2DM) to investigate the effect of two days of oatmeal treatment on BA concentration as compared to a conventional T2DM-adapted diet.

Methods: The OatMeal And Insulin Resistance study was performed as a randomized, open label crossover dietary intervention study with consecutive inclusion of 15 patients in an inpatient clinical setting. Bile acids were measured by high-resolution mass spectrometry. For statistical analysis, the differences in the concentration of serum BA and laboratory parameters between the fifth day and the third day of each inpatient stay were calculated and the effect compared between both phases by using the Wilcoxon test.

Results: Whereas there was a mean decrease in total BA following oatmeal treatment (-0.82±1.14 µmol/l), there was no decrease following the control treatment. Glycocholic acid was lower after oatmeal treatment but higher following control treatment (-0.09±0.17 vs. 0.05±0.11 µmol/l). The reduction in total BA was directly correlated with a decrease in proinsulin during the oatmeal phase. Decreases in blood lipids or apolipoproteins were mostly greater after oatmeal treatment, but these differences were not statistically significant.

Conclusion: Two days of oatmeal diet led to significant reductions in total BA as compared to a diabetes-adapted control diet. The magnitude of BA reduction was directly correlated with a decrease in proinsulin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1069-7330DOI Listing
September 2020

Hypoglycaemia leads to a delayed increase in platelet and coagulation activation markers in people with type 2 diabetes treated with metformin only: Results from a stepwise hypoglycaemic clamp study.

Diabetes Obes Metab 2020 02 3;22(2):212-221. Epub 2019 Nov 3.

Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.

Aims: To investigate the effect of hypoglycaemia on platelet and coagulation activation in people with type 2 diabetes.

Materials And Methods: This monocentric, open, single-arm, mechanistic trial included 14 people with established type 2 diabetes (four women, 10 men, age 55 ± 7 years, glycated haemoglobin concentration 51 ± 7 mmol/mol) receiving metformin monotherapy. A stepwise hyperinsulinaemic-hypoglycaemic clamp experiment (3.5 and 2.5 mmol/L, for 30 minutes respectively) was performed, aiming to investigate platelet and coagulation activity during predefined plateaus of hypoglycaemia, as well as 1 day and 7 days later.

Results: While platelet activation assessed by light transmittance aggregometry did not significantly increase after the hypoglycaemic clamp procedure, the more sensitive flow cytometry-based measurement of platelet surface activation markers showed hypoglycaemia-induced activation 24 hours (PAC1 CD62P , PAC1 CD63P and PAC1 CD62P CD63 ; P < .01) and 7 days after the hypoglycaemic clamp (P < .001 for PAC1 CD63 ; P < .01 for PAC1 CD62P and PAC1 CD62P CD63 ) in comparison to baseline. Coagulation markers, such as fibrinogen, D-dimer, plasminogen activator inhibitor-1, von Willebrand factor activity and factor VIII, were also significantly increased, an effect that was most pronounced 24 hours after the hypoglycaemic clamp.

Conclusion: A single event of insulin-induced hypoglycaemia led to an increase in markers of platelet activation and coagulation in people with early stages of type 2 diabetes on metformin therapy. However, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycaemic episode.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.13889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972619PMC
February 2020

Association of soluble CD40L with short-term and long-term cardiovascular and all-cause mortality: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Atherosclerosis 2019 12 14;291:127-131. Epub 2019 Sep 14.

5th Medical Department, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany. Electronic address:

Background And Aims: The CD40CD40 Ligand (CD40L) system has an important role in vascular inflammation. For this reason, we assessed the association of soluble CD40L with cardiovascular and all-cause mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Methods: Plasma levels of sCD40L were determined in 2759 persons using an enzyme immunoassay. Cox proportional hazard regressions were performed to evaluate the association between plasma concentration of sCD40 ligand and short-term (12 months) and long-term (10 years) mortality. Subpopulation analyses were conducted in seven different risk groups. Cox regression models were adjusted for traditional risk factors.

Results: The present study did not reveal significant association between sCD40L plasma levels and all-cause mortality, as well as cardiovascular mortality at one-year follow-up. In selected subgroups only, significant association between elevated sCD40L plasma levels and short-term all-cause and cardiovascular mortality could be observed. With regard to long-term all-cause and cardiovascular mortality analyses, no significant correlation with increased plasma levels of sCD40L could be detected, neither overall nor in any subgroup.

Conclusions: Soluble sCD40L is not associated with cardiovascular and all-cause mortality in this large cohort. Only in selected patient subgroups elevated levels of sCD40L correlate with short-term mortality but this correlation disappears in long-term analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2019.09.004DOI Listing
December 2019

Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis.

Hepatology 2020 05 30;71(5):1750-1765. Epub 2019 Dec 30.

Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background And Aims: Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy.

Approach And Results: To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2 ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2 mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation.

Conclusions: Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317927PMC
May 2020

Comparison of lipoprotein (a) serum concentrations measured by six commercially available immunoassays.

Atherosclerosis 2019 10 27;289:206-213. Epub 2019 Aug 27.

Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg, Germany.

Background And Aims: Lipoprotein (a) [Lp(a)] is an established causal risk factor for cardiovascular disease (CVD), independently of low-density lipoproteins (LDL) and other risk factors. The recognition of Lp(a) as an atherogenic molecule has raised the demand for reliable quantification methods in the clinical laboratory. The aim of this work is to compare commercial immunochemical assays.

Methods: We measured Lp(a) serum concentrations using six different assays, providing Lp(a) in mg/dl (Denka Seiken, Abbott Quantia, Beckman, Diasys 21FS, and Siemens N Latex) or in nmol/l (Roche TinaQuant, Diasys 21 FS) in 144 serum samples covering the clinically relevant range of Lp(a) concentrations. All assays relied on five-point calibrations using calibrators provided by the manufacturers. Apolipoprotein(a) phenotyping was performed by sodium dodecyl sulfate-agarose gel electrophoresis (SDS-agarose) followed by immunoblotting.

Results: Most bivariate correlation coefficients were greater than 0.90. Compared to an established IFCC-proposed reference material, the results of the different assays diverged from the target values (43.3 mg/dl or 96.6 nmol/l) by -8% (Siemens N Latex) and +22% (Abbott Quantia). Stratification of the samples into five groups with increasing Lp(a) concentrations and difference plots showed that the differences among assays were concentration-dependent. Some assays overestimated Lp(a) at high concentrations compared to the Denka Seiken assay.

Conclusions: Current commercial immunological assays for measuring Lp(a) concentrations are differently calibrated. Their biases differ significantly across the clinically relevant concentration range in a non-linear manner. This is not conclusively explained by apolipoprotein (a) phenotypes. Further international efforts to harmonize assays for Lp(a) are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2019.08.015DOI Listing
October 2019
-->