Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs... Show moreCarboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value = 0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half‐maximal inhibitory concentration (IC50) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 μM, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme. Show less
Nahon, K.J.; Kantae, V.; Haan, R. den; Hanssen, M.J.W.; Harms, A.C.; Stelt, M. van der; ... ; Boon, M.R. 2018
The study aimed to investigate whether markers of endocannabinoid signaling differed between men with overweight of South Asian and white Caucasian descent. We included South Asian (n = 10) and... Show moreThe study aimed to investigate whether markers of endocannabinoid signaling differed between men with overweight of South Asian and white Caucasian descent. We included South Asian (n = 10) and white Caucasian (n = 10) men with overweight and prediabetes aged 35 to 50 years. Plasma samples were analyzed for endocannabinoids, their congeners, and lipids. In white adipose tissue (WAT) and skeletal muscle biopsies, mRNA expression of genes involved in the endocannabinoid system (ECS) was assessed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Fasting lipid oxidation and glucose oxidation were determined with indirect calorimetry. was 10-fold lower (P < 0.001) and that of the endocannabinoid degradation enzyme fatty acid amide hydrolase 2 (FAAH2) was 5-fold lower (P < 0.001) compared to white Caucasians. Expression of genes involved in the ECS in WAT were not different between the two ethnicities. After pooling of both ethnicities, plasma 2-arachidonoylglycerol (2-AG) positively correlated with plasma triglycerides (R = 0.77, P < 0.001) and lipid oxidation (R = 0.55, P < 0.05). South Asian men with overweight have higher plasma 2-linoleoyl glycerol and N-linoleoylethanolamine levels and lower expression of CB receptors and the endocannabinoid degradation enzyme FAAH2 in skeletal muscle compared to white Caucasians. OBJECTIVE METHODS RESULTS CONCLUSIONS Show less
Schoeman, J.C.; Harms, A.C.; Weeghel, M. van; Berger, R.; Vreeken, R.J.; Hankemeier, T. 2018
Oxidative stress and inflammation are underlying pathogenic mechanisms associated with the progression of several pathological conditions and immunological responses. Elucidating the role of... Show moreOxidative stress and inflammation are underlying pathogenic mechanisms associated with the progression of several pathological conditions and immunological responses. Elucidating the role of signalling lipid classes, which include, among others, the isoprostanes, nitro fatty acids, prostanoids, sphingoid bases and lysophosphatidic acids, will create a snapshot of the cause and effect of inflammation and oxidative stress at the metabolic level. Here we describe a fast, sensitive, and targeted ultra-high-performance liquid chromatography-tandem mass spectrometry metabolomics method that allows the quantitative measurement and biological elucidation of 17 isoprostanes as well as their respective isomeric prostanoid mediators, three nitro fatty acids, four sphingoid mediators, and 24 lysophosphatidic acid species from serum as well as organ tissues, including liver, lung, heart, spleen, kidney and brain. Application of this method to paired mouse serum and tissue samples revealed tissue- and serum-specific stress and inflammatory readouts. Little correlation was found between localized (tissue) metabolite levels compared with the systemic (serum) circulation in a homeostatic model. The application of this method in future studies will enable us to explore the role of signalling lipids in the metabolic pathogenicity of stress and inflammation during health and disease. Show less
The Chinese medicine Qiliqiangxin (QL) has been shown to have a protective role in heart failure. Here, we explore the underlying working mechanism of the key therapeutic component in QL using a... Show moreThe Chinese medicine Qiliqiangxin (QL) has been shown to have a protective role in heart failure. Here, we explore the underlying working mechanism of the key therapeutic component in QL using a rat model of heart failure. Heart failure after myocardial infarction was induced surgically and confirmed using echocardiography; a separate group of rats underwent sham surgery. The rats with heart failure were randomly assigned to receive QL, the angiotensin-converting enzyme inhibitor benazepril, or placebo groups. Blood samples were collected from the rats at four time points for up to 8 weeks and used for biochemical analysis and mass spectrometry‒based metabolomics profiling. In total, we measured nine well-known biochemical parameters of heart failure and 147 metabolites. In the rats with heart failure, QL significantly improved these biochemical parameters and metabolomics profiles, significantly increasing the cardioprotective parameter angiopoietin-like 4 and significantly lowering inflammation-related oxylipins and lysophosphatidic acids compared to benazepril. Mechanistically, QL may improve outcome in heart failure by controlling inflammatory process and cardiac hypertrophy. Clinical studies should be designed in order to investigate these putative mechanisms in patients. Show less
Background/ObjectivesEndocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes... Show moreBackground/ObjectivesEndocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac function is still unknown. Therefore, our aim was to investigate this relationship in obese T2D patients with coronary artery disease (CAD).Subjects/MethodsIn a prospective intervention study, obese T2D patients with CAD (n = 27) followed a 16 week very low calorie diet (VLCD; 450–1000 kcal/day). Cardiac function and fat accumulation were assessed with MRI and spectroscopy. Plasma levels of lipid species, including ECs, were measured using liquid chromatography-mass spectrometry.ResultsVLCD decreased plasma levels of virtually all measured lipid species of the class of N-acylethanolamines including the EC anandamide (AEA; −15%, p = 0.016), without decreasing monoacylglycerols including the EC 2-arachidonoylglycerol (2-AG). Baseline plasma AEA levels strongly correlated with the volume of subcutaneous white adipose tissue (SAT; R2 = 0.44, p < 0.001). VLCD decreased the volume of SAT (−53%, p < 0.001), visceral white adipose tissue (VAT) (−52%, p < 0.001), epicardial white adipose tissue (−15%, p < 0.001) and paracardial white adipose tissue (−28%, p < 0.001). VLCD also decreased hepatic (−86%, p < 0.001) and myocardial (−33%, p < 0.001) fat content. These effects were accompanied by an increased left ventricular ejection fraction (54.8 ± 8.7–56.2 ± 7.9%, p = 0.016).ConclusionsCaloric restriction in T2D patients with CAD decreases AEA levels, but not 2-AG levels, which is paralleled by decreased lipid accumulation in adipose tissue, liver and heart, and improved cardiovascular function. Interestingly, baseline AEA levels strongly correlated with SAT volume. We anticipate that dietary interventions are worthwhile strategies in advanced T2D, and that reduction in AEA may contribute to the improved cardiometabolic phenotype induced by weight loss. Show less
Schoeman, J.C.; Harms, A.C.; Weeghel, M. van; Berger, R.; Vreeken, R.J.; Hankemeier, T. 2018
Oxidative stress and inflammation are underlying pathogenic mechanisms associated with the progression of several pathological conditions and immunological responses. Elucidating the role of... Show moreOxidative stress and inflammation are underlying pathogenic mechanisms associated with the progression of several pathological conditions and immunological responses. Elucidating the role of signalling lipid classes, which include, among others, the isoprostanes, nitro fatty acids, prostanoids, sphingoid bases and lysophosphatidic acids, will create a snapshot of the cause and effect of inflammation and oxidative stress at the metabolic level. Here we describe a fast, sensitive, and targeted ultra-high-performance liquid chromatography-tandem mass spectrometry metabolomics method that allows the quantitative measurement and biological elucidation of 17 isoprostanes as well as their respective isomeric prostanoid mediators, three nitro fatty acids, four sphingoid mediators, and 24 lysophosphatidic acid species from serum as well as organ tissues, including liver, lung, heart, spleen, kidney and brain. Application of this method to paired mouse serum and tissue samples revealed tissue- and serum-specific stress and inflammatory readouts. Little correlation was found between localized (tissue) metabolite levels compared with the systemic (serum) circulation in a homeostatic model. The application of this method in future studies will enable us to explore the role of signalling lipids in the metabolic pathogenicity of stress and inflammation during health and disease. Show less
Brink, W.J. van den; Elassaiss, J.; Gonzalez Amoros, B.; Harms, A.C.; Graaf, P.H. van der; Hankemeier, T.; Lange, E.C.M. de 2017
Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on... Show moreMendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for nonspecific effects. We focused on 124 circulating metabolites that correlate with fasting glucose in the Erasmus Rucphen Family (ERF) study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected 14 paths with potential causal effects by MR, following pathway-based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose levels and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated HDL components, i.e., small HDL triglycerides, might have a causal role of elevating glucose levels. In contrast, large (L) and extra large (XL) HDL lipid components, i.e., XL-HDL cholesterol, XL-HDL–free cholesterol, XL-HDL phospholipids, L-HDL cholesterol, and L-HDL–free cholesterol, as well as HDL cholesterol seem to be protective against increasing fasting glucose but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high-resolution metabolomics over classic biochemistry. Show less
Toledo, J.B.; Arnold, M.; Kastenmüller, G.; Chang, R.; Baillie, R.A.; Han, X.; ... ; Kaddurah-Daouk, R. 2017
IntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our... Show moreIntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.MethodsFasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.DiscussionMetabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. Show less
Liu, J.; Semiz, S.; Lee, S.J. van der; Spek, A. van der; Verhoeven, A.; Klinken, J.B.; ... ; Demirkan, A. 2017
South Asians have a higher risk to develop obesity and related disorders compared to white Caucasians. This is likely in part due to their lower resting energy expenditure (REE) as related with... Show moreSouth Asians have a higher risk to develop obesity and related disorders compared to white Caucasians. This is likely in part due to their lower resting energy expenditure (REE) as related with less energy-combusting brown adipose tissue (BAT). Since overactivation of the endocannabinoid system is associated with obesity and low BAT activity, we hypothesized that South Asians have a higher endocannabinoid tone. Healthy lean white Caucasian (n = 10) and South Asian (n = 10) men were cold-exposed to activate BAT. Before and after cooling, REE was assessed and plasma was collected for analysis of endocannabinoids and lipids. At thermoneutrality, South Asians had higher plasma levels of 2-arachidonoylglycerol (2-AG; 11.36 vs 8.19 pmol/mL, p < 0.05), N-arachidonylethanolamine (AEA; 1.04 vs 0.89 pmol/mL, p = 0.05) and arachidonic acid (AA; 23.24 vs 18.22 nmol/mL, p < 0.001). After pooling of both ethnicities, plasma 2-AG but not AEA positively correlated with triglycerides (R2 = 0.32, p < 0.05) and body fat percentage (R2 = 0.18, p < 0.05). Interestingly, AA negative correlated with REE (R2 = 0.46, p < 0.001) and positively with body fat percentage (R2 = 0.33, p < 0.01). Cooling increased endocannabinoids. In conclusion, South Asian compared to white Caucasian men have higher endocannabinoid tone. This suggests that endocannabinoids may, at least in part, underlie the disadvantageous metabolic phenotype of South Asians later in life. Show less
