The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol,... Show moreThe liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model. Show less
Purpose The duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not... Show morePurpose The duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not good predictors of the onset or progression of diabetic retinopathy (DR). Therefore, we aimed to investigate the differences in the serum lipid composition in patients with T2DM, without and with DR, and search for potential serological indicators associated with the development of DR. Methods A total of 622 patients with T2DM hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Xi’an JiaoTong University were selected as the discovery set. One-to-one case–control matching was performed according to the traditional risk factors for DR (i.e., age, duration of diabetes, HbA1c level, and hypertension). All cases with comorbid chronic kidney disease were excluded to eliminate confounding factors. A total of 42 pairs were successfully matched. T2DM patients with DR (DR group) were the case group, and T2DM patients without DR (NDR group) served as control subjects. Ultra-performance liquid chromatography–mass spectrometry (LC–MS/MS) was used for untargeted lipidomics analysis on serum, and a partial least squares discriminant analysis (PLS-DA) model was established to screen differential lipid molecules based on variable importance in the projection (VIP)>1. An additional 531 T2DM patients were selected as the validation set. Next, 1:1 propensity score matching (PSM) was performed for the traditional risk factors for DR, and a combined 95 pairings in the NDR and DR groups were successfully matched. The screened differential lipid molecules were validated by multiple reaction monitoring (MRM) quantification based on mass spectrometry. Results The discovery set showed no differences in traditional risk factors associated with the development of DR (i.e., age, disease duration, HbA1c, blood pressure, and glomerular filtration rate). In the DR group compared Show less
Schaftenaar, F.H.; Dam, A.D. van; Bruin, G. de; Depuydt, M.A.C.; Mol, J.; Amersfoort, J.; ... ; Kuiper, J. 2024
Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is... Show moreAtherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects.We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit β5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit β1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice.ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose.We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment. Show less
Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with... Show moreSepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae–induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis. Show less
Obesity is a complex multicausal disease that can cause morbidity and mortality, and there is need for improved knowledge on the underlying mechanisms. Using a mouse model of increased T cell... Show moreObesity is a complex multicausal disease that can cause morbidity and mortality, and there is need for improved knowledge on the underlying mechanisms. Using a mouse model of increased T cell responsiveness, we show that development of obesity can be driven by immune cells. This was confirmed with bone marrow transplantation and adoptive T cell transfer to several recipient mouse models. Single-cell RNA sequencing and CyTOF analysis showed that the mice display altered composition of circulating T cells and increased T cell activation in visceral adipose tissue, suggesting activated T cells as critical players in the increased fat mass. In this study, we provide evidence that obesity can be driven by immune cell activity and in particular by T cells, which could have broad implications for prevention and treatment of this condition. Show less
Cofino-Fabres, C.; Boonen, T.; Rivera-Arbelaez, J.M.; Rijpkema, M.; Blauw, L.; Rensen, P.C.N.; ... ; Passier, R. 2024
Advanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety... Show moreAdvanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety pharmacology. Conventional 3D Engineered Heart Tissues (EHTs) lack heterotypic cell complexity and culture under flow, whereas microfluidic Heart-on-Chip (HoC) models in general lack the 3D configuration and accurate contractile readouts. In this study, an innovative and user-friendly HoC model is developed to overcome these limitations, by culturing human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs), endothelial (ECs)- and smooth muscle cells (SMCs), together with human cardiac fibroblasts (FBs), underflow, leading to self-organized miniaturized micro-EHTs (µEHTs) with a CM-EC interface reminiscent of the physiological capillary lining. µEHTs cultured under flow display enhanced contractile performance and conduction velocity. In addition, the presence of the EC layer altered drug responses in µEHT contraction. This observation suggests a potential barrier-like function of ECs, which may affect the availability of drugs to the CMs. These cardiac models with increased physiological complexity, will pave the way to screen for therapeutic targets and predict drug efficacy. 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
Li, S.; Ying, Z.X.; Gentenaar, M.; Rensen, P.C.N.; Kooijman, S.; Visser, J.A.; ... ; Kroon, J. 2023
Context Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased... Show moreContext Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure.Objective We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS.Methods In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms.Results We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated Hsd11b1, which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues.Conclusion We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice. Show less
Li, M.H.; Noordam, R.; Winter, E.M.; Meurs, M. van; Bouma, H.R.; Arbous, M.S.; ... ; Kooijman, S. 2023
Purpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in... Show morePurpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in the prevention of death in septic patients. Here we evaluated the association between hydrocortisone treatment and mortality in patients diagnosed with sepsis in a large-scale clinical dataset.Methods: Data from patients between 2008 and 2019 were extracted from the retrospective Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients who received hydrocortisone after diagnosis were matched using propensity-score matching with patients who did not, to balance confounding (by indication and contraindication) factors between the groups. 90-day mortality and survivors' length of hospital stay was compared between patients who did or did not receive hydrocortisone.Results: A total of 31,749 septic patients were included in the study (mean age: 67, men: 57.3%, in-hospital mortality: 15.6%). 90-day mortality was higher among the 1802 patients receiving hydrocortisone when compared with the 6348 matched non-users (hazard ratio: 1.35, 95% CI: 1.24-1.47). Hydrocortisone treatment was also associated with increased in-hospital mortality (40.9% vs. 27.6%, p < 0.0001) and prolonged hospital stay in those who survived until discharge (median 12.6 days vs. 10.8 days, p < 0.0001). Stratification for age, gender, ethnicity, occurrence of septic shock, and the need for vasopressor drug administration such as (nor) epinephrine did not reveal sub-population(s) benefiting of hydrocortisone use.Conclusion: Hydrocortisone treatment is associated with increased risk of death as well as prolonged hospital stay in septic patients. Although residual confounding (by indication) cannot be ruled out completely due to the observational nature of the study, the present study suggests clinical implication of hydrocortisone use in patients with sepsis. Show less
ContextThe endocannabinoid system (ECS) is a signaling system composed of endocannabinoids (eCBs), their receptors, and the enzymes involved in their synthesis and metabolism. Alterations in the... Show moreContextThe endocannabinoid system (ECS) is a signaling system composed of endocannabinoids (eCBs), their receptors, and the enzymes involved in their synthesis and metabolism. Alterations in the ECS are linked to the development of cardiometabolic diseases.ObjectiveHere, we investigated the relationship between plasma levels of eCBs and their analogues with body composition and cardiometabolic risk factors.MethodsThe study included 133 young adults (age 22.1 ± 2.2 years, 67% women). Fasting plasma levels of eCBs and their analogues were measured using liquid chromatography-tandem mass spectrometry. Body composition, brown adipose tissue (BAT) volume, glucose uptake, and traditional cardiometabolic risk factors were measured.ResultsPlasma levels of eCBs and several eCB analogues were positively correlated with adiposity and traditional cardiometabolic risk factors (eg, serum insulin and triacylglyceride levels, all r ≥ 0.17 and P ≤ .045). Plasma levels of 2-arachidonoyl glycerol and N-pentadecenoylethanolamine were negatively correlated with BAT volume and glucose uptake (all r ≤ −0.17 and P ≤ .047). We observed that the plasma levels of eCBs and their analogues were higher in metabolically unhealthy overweight–obese participants than in metabolically healthy overweight–obese participants.ConclusionOur findings show that the plasma levels of eCBs and their analogues are related to higher levels of adiposity and worse cardiometabolic profile. Show less
The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with aging. Although CD40 is mainly expressed by immune cells, CD40 is also present on... Show moreThe co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with aging. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte CD40 in the aging hematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow hematopoietic stem cells (Lin–Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased bone marrow adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE–/– (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in bone marrow, spleen, and adipose tissue, while the numbers of B cells were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T cells and larger necrotic cores. Analysis of peripheral adipose tissue in a diet-induced model of obesity revealed that obese AdiCD40KO mice had increased T-cell activation in adipose tissue and lymphoid organs, but decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in bone marrow during aging and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40 deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases. Show less
Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by & UDelta... Show moreLiver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by & UDelta;24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRa deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRa-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH. Show less
Ying, Z.X.; Eenige, R. van; Ge, X.K.; Marwijk, C. van; Lambooij, J.M.; Guigas, B.; ... ; Kooijman, S. 2023
BackgroundCombined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic... Show moreBackgroundCombined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development.MethodsMale APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day.FindingsGIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury.InterpretationWe interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans. Show less
Panhuis, W. in het; Schönke, M.; Modder, M.; Tom, H.E.; Lalai, R.A.; Pronk, A.C.M.; ... ; Kooijman, S. 2023
Circadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift work has... Show moreCircadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift work has been associated with elevated risk for atherosclerotic cardiovascular disease (asCVD) in humans, but evidence for the effectiveness of prevention strategies is lacking.\nHere, we applied time-restricted feeding (TRF) as a strategy to counteract atherosclerosis development during CD in female APOE∗3-Leiden.CETP mice, a well-established model for humanized lipoprotein metabolism. Control groups were subjected to a fixed 12:12 h light-dark cycle, while CD groups were subjected to 6-h phase advancement every 3 days. Groups had either ad libitum (AL) access to food or were subjected to TRF with restricted food access to the dark phase.\nTRF did not prevent the increase in the relative abundance of circulating inflammatory monocytes and elevation of (postprandial) plasma triglycerides during CD. Nonetheless, TRF reduced atherosclerotic lesion size and prevented an elevation in macrophage content of atherosclerotic lesions during CD, while it increased the relative abundance of anti-inflammatory monocytes, prevented activation of T cells, and lowered plasma total cholesterol levels and markers of hepatic cholesterol synthesis. These effects were independent of total food intake.\nWe propose that time restricted eating could be a promising strategy for the primary prevention of asCVD risk in shift workers, which warrants future study in humans.\nThis work was funded by the Novo Nordisk Foundation, the Netherlands Ministry of Social Affairs and Employment, Amsterdam Cardiovascular Sciences, and the Dutch Heart Foundation. Show less
Panhuis, W.I.H.; Schönke, M.; Modder, M.; Tom, H.E.; Lalai, R.A.; Pronk, A.C.M.; ... ; Kooijmana, S. 2023
BackgroundCircadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift... Show moreBackgroundCircadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift work has been associated with elevated risk for atherosclerotic cardiovascular disease (asCVD) in humans, but evidence for the effectiveness of prevention strategies is lacking.MethodsHere, we applied time-restricted feeding (TRF) as a strategy to counteract atherosclerosis development during CD in female APOE∗3-Leiden.CETP mice, a well-established model for humanized lipoprotein metabolism. Control groups were subjected to a fixed 12:12 h light–dark cycle, while CD groups were subjected to 6-h phase advancement every 3 days. Groups had either ad libitum (AL) access to food or were subjected to TRF with restricted food access to the dark phase.FindingsTRF did not prevent the increase in the relative abundance of circulating inflammatory monocytes and elevation of (postprandial) plasma triglycerides during CD. Nonetheless, TRF reduced atherosclerotic lesion size and prevented an elevation in macrophage content of atherosclerotic lesions during CD, while it increased the relative abundance of anti-inflammatory monocytes, prevented activation of T cells, and lowered plasma total cholesterol levels and markers of hepatic cholesterol synthesis. These effects were independent of total food intake.InterpretationWe propose that time restricted eating could be a promising strategy for the primary prevention of asCVD risk in shift workers, which warrants future study in humans.FundingThis work was funded by the Novo Nordisk Foundation, the Netherlands Ministry of Social Affairs and Employment, Amsterdam Cardiovascular Sciences, and the Dutch Heart Foundation. Show less
Kovynev, A.; Ying, Z.X.; Lambooij, J.M.; Zande, H.J.P. van der; Guigas, B.; Rensen, P.C.N.; Schonke, M. 2023
Circulating bile acids (BA) are signaling molecules that control glucose and lipid metabolism. However, the effects of acute exercise on plasma levels of BA in humans remain poorly understood. Here... Show moreCirculating bile acids (BA) are signaling molecules that control glucose and lipid metabolism. However, the effects of acute exercise on plasma levels of BA in humans remain poorly understood. Here, we evaluate the effects of a bout of maximal endurance exercise (EE) and resistance exercise (RE) on plasma levels of BA in young, sedentary adults. Concentration of eight plasma BA was measured by liquid chromatography--tandem mass spectrometry before and 3, 30, 60, and 120 min after each exercise bout. Cardiorespiratory fitness (CRF) was assessed in 14 young adults (21.8 +/- 2.5 yo, 12 women); muscle strength was assessed in 17 young adults (22.4 +/- 2.5 yo, 11 women). EE transiently decreased plasma levels of total, primary, and secondary BA at 3 and 30 min after exercise. RE exerted a prolonged reduction in plasma levels of secondary BA (p < 0.001) that lasted until 120 min. Primary BA levels of cholic acid (CA) and chenodeoxycholic acid (CDCA) were different across individuals with low/high CRF levels after EE (p = 0.044); CA levels were different across individuals with low/high handgrip strength levels. High CRF individuals presented higher levels of CA and CDCA 120 min after exercise vs baseline (+77% and +65%) vs the low CRF group (-5% and -39%). High handgrip strength levels individuals presented higher levels of CA 120 min after exercise versus baseline (+63%) versus the low handgrip strength group (+6%). The study findings indicate that an individual's level of physical fitness can influence how circulating BA respond to both endurance and resistance exercise. Additionally, the study suggests that changes in plasma BA levels after exercising could be related to the control of glucose homeostasis in humans. Show less
Background: Gut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is... Show moreBackground: Gut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is poorly understood. Here, we investigated the relationship between fecal microbiota diversity and composition with plasma levels of BA in young adults. Methods: Fecal microbiota diversity/composition was analyzed with 16S rRNA sequencing in 80 young adults (74% women; 21.9 +/- 2.2 years old). Plasma levels of BA were measured using liquid chromatography-tandem mass spectrometry. PERMANOVA and Spearman correlation analyses were used to investigate the association between fecal microbiota parameters and plasma levels of BA. Results: Fecal microbiota beta (P = 0.025) and alpha diversity indexes of evenness (rho = 0.237, P = 0.033), Shannon (rho = 0.313, P = 0.004), and inverse Simpson (rho = 0.283, P = 0.010) were positively associated with plasma levels of the secondary BA glycolithocholic acid (GLCA). The relative abundance of genera belonging to the Firmicutes and Bacteroidetes phyla was positively correlated with plasma levels of GLCA (all rho = 0.225, P = 0.049). However, the relative abundance of species from Firmicutes and Bacteroidetes phyla were negatively correlated with plasma levels of primary and secondary BA (all rho = - 0.220, P = 0.045), except for the relative abundance of Bacteroides vulgatus, Alistipes onderdonkii, and Bacteroides xylanisolvens species (Bacteroidetes phylum) that were positively correlated with the plasma levels of GLCA. Conclusions:The relative abundance of specific fecal bacteria species is associated with plasma levels of BA in young adults. However, further investigations are required to validate whether the composition of the gut microbiota can regulate the plasma concentrations of BA in humans. Show less
BackgroundGut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is poorly... Show moreBackgroundGut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is poorly understood. Here, we investigated the relationship between fecal microbiota diversity and composition with plasma levels of BA in young adults.MethodsFecal microbiota diversity/composition was analyzed with 16S rRNA sequencing in 80 young adults (74% women; 21.9 ± 2.2 years old). Plasma levels of BA were measured using liquid chromatography-tandem mass spectrometry. PERMANOVA and Spearman correlation analyses were used to investigate the association between fecal microbiota parameters and plasma levels of BA.ResultsFecal microbiota beta (P = 0.025) and alpha diversity indexes of evenness (rho = 0.237, P = 0.033), Shannon (rho = 0.313, P = 0.004), and inverse Simpson (rho = 0.283, P = 0.010) were positively associated with plasma levels of the secondary BA glycolithocholic acid (GLCA). The relative abundance of genera belonging to the Firmicutes and Bacteroidetes phyla was positively correlated with plasma levels of GLCA (all rho ≥ 0.225, P ≤ 0.049). However, the relative abundance of species from Firmicutes and Bacteroidetes phyla were negatively correlated with plasma levels of primary and secondary BA (all rho ≤ − 0.220, P ≤ 0.045), except for the relative abundance of Bacteroides vulgatus, Alistipes onderdonkii, and Bacteroides xylanisolvens species (Bacteroidetes phylum) that were positively correlated with the plasma levels of GLCA.ConclusionsThe relative abundance of specific fecal bacteria species is associated with plasma levels of BA in young adults. However, further investigations are required to validate whether the composition of the gut microbiota can regulate the plasma concentrations of BA in humans. Show less