Introduction Totum-070 is a combination of five plant extracts enriched in polyphenols to target hypercholesterolemia, one of the main risk factors for cardiovascular diseases. The aim of this... Show moreIntroduction Totum-070 is a combination of five plant extracts enriched in polyphenols to target hypercholesterolemia, one of the main risk factors for cardiovascular diseases. The aim of this study was to investigate the effects of Totum-070 on cholesterol levels in an animal model of diet-induced hypercholesterolemia.Methods C57BL/6JOlaHsd male mice were fed a Western diet and received Totum-070, or not, by daily gavage (1g/kg and 3g/kg body weight) for 6 weeks.Results The Western diet induced obesity, fat accumulation, hepatic steatosis and increased plasma cholesterol compared with the control group. All these metabolic perturbations were alleviated by Totum-070 supplementation in a dose-dependent manner. Lipid excretion in feces was higher in mice supplemented with Totum-070, suggesting inhibition of intestinal lipid absorption. Totum-070 also increased the fecal concentration of short chain fatty acids, demonstrating a direct effect on intestinal microbiota.Discussion The characterization of fecal microbiota by 16S amplicon sequencing showed that Totum-070 supplementation modulated the dysbiosis associated with metabolic disorders. Specifically, Totum-070 increased the relative abundance of Muribaculum (a beneficial bacterium) and reduced that of Lactococcus (a genus positively correlated with increased plasma cholesterol level). Together, these findings indicate that the cholesterol-lowering effect of Totum-070 bioactive molecules could be mediated through multiple actions on the intestine and gut microbiota. Show less
Yuan, L.S.; Verhoeven, A.; Blomberg, N.; Eyk, H.J. van; Bizino, M.B.; Rensen, P.C.N.; ... ; Berg, B.M. van den 2024
Type 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated... Show moreType 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated lipidomic changes in plasma of Dutch South Asians (DSA) and Dutch white Caucasians (DwC) with and without T2DM and explore their associations with clinical features. Using a targeted quantitative lipidomics platform, monitoring over 1000 lipids across 17 classes, along with 1H NMR based lipoprotein analysis, we studied 51 healthy participants (21 DSA, 30 DwC) and 92 T2DM patients (47 DSA, 45 DwC) from the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction in type 2 dIAbetes mellitus (MAGNA VICTORIA) study. This comprehensive mapping of the circulating lipidome allowed us to identify relevant lipid modules through unbiased weighted correlation network analysis, as well as disease and ethnicity related key mediatory lipids. Significant differences in lipidomic profiles, encompassing various lipid classes and species, were observed between T2DM patients and healthy controls in both the DSA and DwC populations. Our analyses revealed that healthy DSA, but not DwC, controls already exhibited a lipid profile prone to develop T2DM. Particularly, in DSA-T2DM patients, specific lipid changes correlated with clinical features, particularly diacylglycerols (DGs), showing significant associations with glycemic control and renal function. Our findings highlight an ethnic distinction in lipid modules influencing clinical outcomes in renal health. We discover distinctive ethnic disparities of the circulating lipidome and identify ethnicity-specific lipid markers. Jointly, our discoveries show great potential as personalized biomarkers for the assessment of glycemic control and renal function in DSA-T2DM individuals. Show less
BackgroundPolycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a... Show moreBackgroundPolycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD patients, who had participated in a trial on the effect of a somatostatin analogue. Our hypothesis was that serum bile acid levels increase in PLD, and that lanreotide, which reduces liver growth, may also reduce bile acid levels. Furthermore, in PLD, urinary excretion of bile acids might contribute to renal disease.MethodsWith liquid chromatography-mass spectrometry, 11 bile acids in serum and 6 in urine were quantified in 105 PLD ADPKD patients and 52 age-, sex-, mutation- and eGFR-matched non-PLD ADPKD patients. Sampling was done at baseline and after 120 weeks of either lanreotide or standard care.ResultsBaseline serum levels of taurine- and glycine-conjugated bile acids were higher in patients with larger livers. In PLD patients, multiple bile acids decreased upon treatment with lanreotide but remained stable in untreated subjects. Changes over time did not correlate with changes in liver volume. Urine bile acid levels did not change and did not correlate with renal disease progression.ConclusionIn ADPKD patients with PLD, baseline serum bile acids were associated with liver volume. Lanreotide reduced bile acid levels and has previously been shown to reduce liver volume. However, in this study, the decrease in bile acids was not associated with the change in liver volume. Show less
Lipid analysis at the molecular species level represents a valuable opportunity for clinical applications due to the essential roles that lipids play in metabolic health. However, a comprehensive... Show moreLipid analysis at the molecular species level represents a valuable opportunity for clinical applications due to the essential roles that lipids play in metabolic health. However, a comprehensive and high-throughput lipid profiling remains challenging given the lipid structural complexity and exceptional diversity. Herein, we present an 'omic-scale targeted LC-MS/MS approach for the straightforward and high-throughput quantification of a broad panel of complex lipid species across 26 lipid (sub)classes. The workflow involves an automated single-step extraction with 2-propanol, followed by lipid analysis using hydrophilic interaction liquid chromatography in a dual-column setup coupled to tandem mass spectrometry with data acquisition in the timed selective reaction monitoring mode (12 min total run time). The analysis pipeline consists of an initial screen of 1903 lipid species, followed by high-throughput quantification of robustly detected species. Lipid quantification is achieved by a single-point calibration with 75 isotopically labeled standards representative of different lipid classes, covering lipid species with diverse acyl/alkyl chain lengths and unsaturation degrees. When applied to human plasma, 795 lipid species were measured with median intra-and inter-day precisions of 8.5 and 10.9%, respectively, evaluated within a single and across multiple batches. The concentration ranges measured in NIST plasma were in accordance with the consensus intervals determined in previous ring-trials. Finally, to benchmark our workflow, we characterized NIST plasma materials with different clinical and ethnic backgrounds and analyzed a sub-set of sera (n = 81) from a clinically healthy elderly population. Our quantitative lipidomic platform allowed for a clear distinction between different NIST materials and revealed the sex-specificity of the serum lipidome, highlighting numerous statistically significant sex differences. Show less
Gagestein, B.; von Hegedus, J.H.; Kwekkeboom, J.C.; Heijink, M.; Blomberg, N.; Wel, T. van der; ... ; Stelt, M. van der 2022
The fish oil constituent docosahexaenoic acid (DHA, 22:6 n-3) is a signaling lipid with anti-inflammatory properties. The molecular mechanisms underlying the biological effect of DHA are poorly... Show moreThe fish oil constituent docosahexaenoic acid (DHA, 22:6 n-3) is a signaling lipid with anti-inflammatory properties. The molecular mechanisms underlying the biological effect of DHA are poorly understood. Here, we report the design, synthesis, and application of a complementary pair of bio-orthogonal, photoreactive probes based on the polyunsaturated scaffold DHA and its oxidative metabolite 17-hydroxydocosahexaenoic acid (17-HDHA). In these probes, an alkyne serves as a handle to introduce a fluorescent reporter group or a biotin-affinity tag via copper(I)-catalyzed azide-alkyne cycloaddition. This pair of chemical probes was used to map specific targets of the omega-3 signaling lipids in primary human macrophages. Prostaglandin reductase 1 (PTGR1) was identified as an interaction partner that metabolizes 17-oxo-DHA, an oxidative metabolite of 17-HDHA. 17-oxo-DHA reduced the formation of pro-inflammatory lipids 5-HETE and LTB4 in human macrophages and neutrophils. Our results demonstrate the potential of comparative photoaffinity protein profiling for the discovery of metabolic enzymes of bioactive lipids and highlight the power of chemical proteomics to uncover new biological insights. Show less
Gagestein, B.; Hegedus, J.H. von; Kwekkeboom, J.C.; Heijink, M.; Blomberg, N.; Wel, T. van der; ... ; Stelt, M. van der 2022
The fish oil constituent docosahexaenoic acid (DHA, 22:6 n-3) is a signaling lipid with anti-inflammatory properties. The molecular mechanisms underlying the biological effect of DHA are poorly... Show moreThe fish oil constituent docosahexaenoic acid (DHA, 22:6 n-3) is a signaling lipid with anti-inflammatory properties. The molecular mechanisms underlying the biological effect of DHA are poorly understood. Here, we report the design, synthesis, and application of a complementary pair of bio-orthogonal, photoreactive probes based on the polyunsaturated scaffold DHA and its oxidative metabolite 17-hydroxydocosahexaenoic acid (17-HDHA). In these probes, an alkyne serves as a handle to introduce a fluorescent reporter group or a biotin-affinity tag via copper(I)-catalyzed azide-alkyne cycloaddition. This pair of chemical probes was used to map specific targets of the omega-3 signaling lipids in primary human macrophages. Prostaglandin reductase 1 (PTGR1) was identified as an interaction partner that metabolizes 17-oxo-DHA, an oxidative metabolite of 17-HDHA. 17-oxo-DHA reduced the formation of pro-inflammatory lipids 5-HETE and LTB4 in human macrophages and neutrophils. Our results demonstrate the potential of comparative photoaffinity protein profiling for the discovery of metabolic enzymes of bioactive lipids and highlight the power of chemical proteomics to uncover new biological insights. Show less
Peeters, R.; Cuenca-Escalona, J.; Zaal, E.A.; Hoekstra, A.T.; Balvert, A.C.G.; Vidal-Manrique, M.; ... ; Spriel, A.B. van 2022
The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic... Show moreThe importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.Tetraspanin CD37 deficiency has been reported as a prognostic marker for aggressive B-cell lymphoma. Here, the authors show that CD37 interacts with the fatty acid transporter 1 to inhibit palmitate uptake and its deficiency leads to increased fatty acid metabolism which promotes tumorigenesis in B-cell lymphoma. Show less
Differential mobility spectrometry (DMS) is highly useful for shotgun lipidomic analysis because it overcomes difficulties in measuring isobaric species within a complex lipid sample and allows for... Show moreDifferential mobility spectrometry (DMS) is highly useful for shotgun lipidomic analysis because it overcomes difficulties in measuring isobaric species within a complex lipid sample and allows for acyl tail characterization of phospholipid species. Despite these advantages, the resulting workflow presents technical challenges, including the need to tune the DMS before every batch to update compensative voltages settings within the method. The Sciex Lipidyzer platform uses a Sciex 5500 QTRAP with a DMS (SelexION), an LC system configured for direction infusion experiments, an extensive set of standards designed for quantitative lipidomics, and a software package (Lipidyzer Workflow Manager) that facilitates the workflow and rapidly analyzes the data. Although the Lipidyzer platform remains very useful for DMS-based shotgun lipidomics, the software is no longer updated for current versions of Analyst and Windows. Furthermore, the software is fixed to a single workflow and cannot take advantage of new lipidomics standards or analyze additional lipid species. To address this multitude of issues, we developed Shotgun Lipidomics Assistant (SLA), a Python-based application that facilitates DMS-based lipidomics workflows. SLA provides the user with flexibility in adding and subtracting lipid and standard MRMs. It can report quantitative lipidomics results from raw data in minutes, comparable to the Lipidyzer software. We show that SLA facilitates an expanded lipidomics analysis that measures over 1450 lipid species across 17 (sub)classes. Lastly, we demonstrate that the SLA performs isotope correction, a feature that was absent from the original software. Show less
Donis, N.; Jiang, Z.S.; D'Emal, C.; Dulgheru, R.; Giera, M.; Blomberg, N.; ... ; Oury, C. 2021
Aims: Palmitic acid (PA) and oleic acid (OA) are two main dietary fatty acids. Dietary intake of PA has been associated with cardiovascular disease risk, and the effect of OA remains uncertain. Our... Show moreAims: Palmitic acid (PA) and oleic acid (OA) are two main dietary fatty acids. Dietary intake of PA has been associated with cardiovascular disease risk, and the effect of OA remains uncertain. Our study aimed to assess the effect of a short-term intake of lard, as source of PA and OA, on aorta and aortic valve.Methods and Results: Rabbits were fed with two lard-enriched diets, containing either elevated levels of PA or of both PA and OA as compared to chow diet. After 16 weeks of each diet, calcification was observed in the aortic intima and in the aortic valve. The extent of calcification did not differ between the two diets. In contrast, rabbits fed chow diet did not develop any calcification. In blood, PA enrichment resulted in decreased lymphocyte and monocyte counts and increased levels of hemoglobin and haematocrit. Levels of the calcification inhibitor fetuin-A were also diminished, whereas creatinine levels were raised. Of note, none of the diets changed cholesterol levels in LDL or HDL. Comprehensive quantitative lipidomics analysis identified diet-related changes in plasma lipids. Dietary PA enrichment led to a drop of polyunsaturated fatty acids (PUFA), in particular of linoleic acid in cholesteryl esters, triglycerides and diacylglycerols (DAG). Ratios of PA to 18-carbon PUFA in DAG were positively correlated with the extent of aortic valve calcification, and inversely with monocyte counts. PA content in blood correlated with aorta calcification.Conclusions: Regular dietary PA intake induces vascular and valvular calcification independently of traditional risk factors. Our findings raise awareness about PA-rich food consumption and its potential deleterious effect on cardiovascular health. Show less
Eenige, R. van; Ying, Z.; Tambyrajah, L; Pronk, A.C.M.; Blomberg, N.; Giera, M.; ... ; Kooijman, S. 2021
Pharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and... Show morePharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is being explored for a number of therapeutic applications; however, its potency for the treatment of atherosclerotic cardiovascular disease via improvements in lipid metabolism remains unclear. Therefore, here, we aimed to investigate whether inhibition of the endocannabinoid system can attenuate atherosclerosis development through improvement of dyslipidemia. Lean, dyslipidemic female APOE∗3-Leiden.CETP transgenic mice were fed a Western-type diet supplemented with or without the cannabinoid type 1 receptor inverse agonist rimonabant (20 mg·kg body weight-1 day-1) for up to 20 weeks. Plasma lipids and bile acids were determined, and atherosclerotic lesions were scored in the aortic valve region. Rimonabant lowered plasma levels of triglyceride (TG) (-56%) and non-HDL-C (-19%) and increased HDL-C (+57%). These effects were explained by decreased VLDL-TG production (-52%) and accelerated VLDL-TG turnover accompanied by pronounced browning of white adipose tissue. In addition, rimonabant attenuated reverse cholesterol transport (-30%), increased plasma bile acid levels (+160%), and increased hepatic cholesterol accumulation (+88%). Importantly, rimonabant markedly lowered atherosclerotic lesion size (-64%), which coincided with decreased lesion severity (28% vs. 56% severe lesions) and which strongly correlated with non-HDL-C exposure (R2 = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity. Show less
eTRANSAFE is a research project funded within the Innovative Medicines Initiative (IMI), which aims at developing integrated databases and computational tools (the eTRANSAFE ToxHub) that support... Show moreeTRANSAFE is a research project funded within the Innovative Medicines Initiative (IMI), which aims at developing integrated databases and computational tools (the eTRANSAFE ToxHub) that support the translational safety assessment of new drugs by using legacy data provided by the pharmaceutical companies that participate in the project. The project objectives include the development of databases containing preclinical and clinical data, computational systems for translational analysis including tools for data query, analysis and visualization, as well as computational models to explain and predict drug safety events. Show less
Eenige, R. van; Ying, Z.X.; Tambyrajah, L.; Pronk, A.C.M.; Blomberg, N.; Giera, M.; ... ; Kooijman, S. 2021
Pharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and... Show morePharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is being explored for a number of therapeutic applications; however, its potency for the treatment of atherosclerotic cardiovascular disease via improvements in lipid metabolism remains unclear. Therefore, here, we aimed to investigate whether inhibition of the endocannabinoid system can attenuate atherosclerosis development through improvement of dyslipidemia. Lean, dyslipidemic female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet supplemented with or without the cannabinoid type 1 receptor inverse agonist rimonabant (20 mg-kg body weight(-1) day(-1)) for up to 20 weeks. Plasma lipids and bile acids were determined, and atherosclerotic lesions were scored in the aortic valve region. Rimonabant lowered plasma levels of triglyceride (TG) (-56%) and non-HDL-C (-19%) and increased HDL-C (+57%). These effects were explained by decreased VLDL-TG production (-52%) and accelerated VLDL-TG turn-over accompanied by pronounced browning of white adipose tissue. In addition, rimonabant attenuated reverse cholesterol transport (-30%), increased plasma bile acid levels (+160%), and increased hepatic cholesterol accumulation (+88%). Importantly, rimonabant markedly lowered atherosclerotic lesion size (-64%), which coincided with decreased lesion severity (28% vs. 56% severe lesions) and which strongly correlated with non-HDL-C exposure (R-2 = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity. Show less
Wilkinson, M.D.; Dumontier, M.; Aalbersberg, I.J.; Appleton, G.; Axton, M.; Baak, A.; ... ; Mons, B. 2019
Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological... Show moreMedicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health arid healthcare for all Europearis. Show less
Wilkinson, M.D.; Dumontier, M.; Aalbersberg, I.J.; Appleton, G.; Axton, M.; Baak, A.; ... ; Mons, B. 2016
