RATIONALE:COpper Metabolism MURR1 Domain-containing (COMMD) proteins are a part of the COMMD-CCDC22-CCDC93 (CCC) complexes facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 ...inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the low-density lipoprotein receptor (LDLR), and increases plasma LDL cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1, and whether perturbation in the CCC complex promotes atherogenesis remain unclear.
OBJECTIVE:To unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis.
METHODS AND RESULTS:Using liver specific Commd1, Commd6 or Commd9 knockout mice we investigated the relation between the COMMD proteins in the regulation of plasma cholesterol levels. Combining biochemical and quantitative targeted proteomic approaches, we found that either hepatic COMMD1, COMMD6 or COMMD9 deficiency resulted in massive reduction in the protein levels of all ten COMMDs. This decrease in COMMD proteins levels coincided with destabilizing of the core (CCDC22, CCDC93, C16orf62) of the CCC complex, reduced cell surface levels of LDLR and LRP1, followed by increased plasma LDL cholesterol levels. To assess the direct contribution of the CCC core in the regulation of plasma cholesterol levels, Ccdc22 was deleted in mouse livers via CRISPR/Cas9-mediated somatic gene editing. CCDC22 deficiency also destabilized the complete CCC complex, and resulted in elevated plasma LDL cholesterol levels. Finally, we found that hepatic disruption of the CCC complex exacerbates dyslipidemia and atherosclerosis in ApoE3*Leiden mice.
CONCLUSIONS:Collectively, these findings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR trafficking. Hepatic disruption of either of these CCC components causes hypercholesterolemia, and exacerbates atherosclerosis. Our results indicate that not only COMMD1, but all other COMMDs and CCC components may be potential targets for modulating plasma lipid levels in humans.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in ...NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.
Background
Disturbances in habitual sleep have been associated with multiple age‐associated diseases. However, the biological mechanisms underpinning these associations remain largely unclear. We ...assessed the possible involvement of the circulating immune system by determining the associations between sleep traits and white blood cell counts using multivariable‐adjusted linear regression and Mendelian randomization.
Methods
Cross‐sectional multivariable‐adjusted linear regression analyses were done using participants within the normal range of total white blood cell counts (>4.5 × 109 and <11.0 × 109/μL) from UK Biobank. For the sleep traits, we examined (short and long) sleep duration, chronotype, insomnia symptoms and daytime dozing. Two‐sample Mendelian randomization analyses were done using instruments for sleep traits derived from European‐ancestry participants from UK Biobank (over 410,000 participants) and using SNP‐outcome data derived from European‐ancestry participants from the Blood Cell Consortium (N = 563,946) to which no data from UK Biobank contributed.
Results
Using data from 357,656 participants (mean standard deviation age: 56.5 8.1 years, and 44.4% men), we did not find evidence that disturbances in any of the studied sleep traits were associated with differences in blood cell counts (total, lymphocytes, neutrophiles, eosinophiles and basophiles). Also, we did not find associations between disturbances in any of the studied sleep traits and white blood cell counts using Mendelian Randomization.
Conclusion
Based on the results from two different methodologies, disturbances in habitual sleep are unlikely to cause changes in blood cell counts and thereby differences in blood cell counts are unlikely to be underlying the observed sleep‐disease associations.
Aims/hypothesis
Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ...ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in
Angptl4
−/−
mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity.
Methods
We chronically fed wild-type (WT) and
Angptl4
−/−
mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests.
Results
Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between
Angptl4
−/−
mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and
Angptl4
−/−
mice.
Conclusions/interpretation
Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism.
ABSTRACT
Chronic low‐grade inflammation associated with obesity contributes to insulin resistance and type 2 diabetes. Helminth parasites are the strongest natural inducers of type 2 immune ...responses, and short‐lived infection with rodent nematodes was reported to improve glucose tolerance in obese mice. Here, we investigated the effects of chronic infection (12 weeks) with Schistosoma mansoni, a helminth that infects millions of humans worldwide, on whole‐body metabolic homeostasis and white adipose tissue (WAT) immune cell composition in high‐fat diet‐induced obese C57BL/6 male mice. Our data indicate that chronic helminth infection reduced body weight gain (‐62%), fat mass gain (‐89%), and adipocyte size; lowered whole‐body insulin resistance (‐23%) and glucose intolerance (‐16%); and improved peripheral glucose uptake (+25%) and WAT insulin sensitivity. Analysis of immune cell composition by flow cytometry and quantitative PCR (qPCR) revealed that S. mansoni promoted strong increases in WAT eosinophils and alternatively activated (M2) macrophages. Importantly, injections with S. mansonir‐soluble egg antigens (SEA) recapitulated the beneficial effect of parasite infection on whole‐body metabolic homeostasis and induced type 2 immune responses in WAT and liver. Taken together, we provide novel data suggesting that chronic helminth infection and helminth‐derived molecules protect against metabolic disorders by promoting a T helper 2 (Th2) response, eosinophilia, and WAT M2 polarization.—Hussaarts, L., García‐Tardón, N., van Beek, L., Heemskerk, M. M., Haeberlein, S., van der Zon, G. C., Ozir‐Fazalalikhan, A., Berbée, J. F. P., Willems van Dijk, K., van Harmelen, V., Yazdanbakhsh, M., Guigas, B. Chronic helminth infection and helminth‐derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J. 29, 3027‐3039 (2015). www.fasebj.org
Low socioeconomic status (SES) is associated with cardiovascular risk factors and increased coronary artery disease (CAD) risk. We tested whether SES is an effect modifier of the association between ...classical cardiovascular risk factors and CAD using SES-stratified Mendelian Randomization in European-ancestry participants from UK Biobank.
We calculated weighted genetic risk scores (GRS) for the risk factors body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, and triglycerides. Participants were stratified by Townsend deprivation index score. Logistic regression models were used to investigate associations between GRSs and CAD occurrence. Additionally, stratification based on GRS-adjusted Townsend deprivation index residuals was conducted to correct for possible collider-stratification bias.
In a total sample size of N = 446,485, with 52,946 cases, the risk for CAD per standard deviation increase in genetically influenced BMI was highest in the group with the lowest 25% SES (odds ratio: 1.126, 95% confidence interval: 1.106–1.145; odds ratio: 1.081, 95% confidence interval: 1.059–1.103 in high SES), remaining similar after controlling for possible collider-stratification bias. The effects of genetically influenced systolic blood pressure, low-density lipoprotein cholesterol, and triglyceride on CAD were similar between SES groups.
CAD risk attributable to increased BMI is not homogenous and could be modified by SES. This emphasizes the need of tailor-made approaches for BMI-associated CAD risk reduction.
•Socioeconomic status modifies BMI-associated coronary artery disease risk.•Lower SES showed higher CAD risk attributable to increased BMI.•Tailor-made approaches could optimize CAD disease risk reduction.
Body fat distribution is, next to overall obesity, an important risk factor for cardiometabolic outcomes in the general population. In particular, visceral adipose tissue (VAT) is strongly associated ...with cardiometabolic risk factors. Since it is unclear whether body fat distribution is also important in men and women with obesity we investigated the associations between measures of body fat distribution and cardiometabolic risk factors in men and women with obesity.
In this cross-sectional analysis of obese men and women (BMI≥30 kg/m2) included in the Netherlands Epidemiology of Obesity Study, waist:hip ratio(WHR), waist circumference, and MRI-based abdominal subcutaneous adipose tissue (aSAT) and VAT were determined. Associations between measures of body fat distribution and presence of ≥1 risk factor, such as hypertension or hypertriglyceridemia, were examined using logistic regression analyses; stratified by sex and adjusted for age, ethnicity, education, tobacco smoking, alcohol consumption, physical activity and depending on the association additionally for total body fat or VAT.
We included 2,983 obese individuals (57% women) with a mean age of 56 and standard deviation (SD) of 6 and mean BMI of 34.0 kg/m2 (4.0), after exclusion of individuals with missing values of cardiometabolic risk factors (n = 33). 241 individuals were obese without other cardiometabolic risk factors. In obese women, all measures of body fat distribution except aSAT (OR per SD:0.76, 95%CI: 0.53, 1.10) were associated with having ≥1 cardiometabolic risk factor, of which VAT most strongly associated (5.77; 3.02, 11.01). In obese men, associations of body fat distribution and the presence of cardiometabolic risk factors were attenuated. (e.g. VAT:1.42; 0.84, 2.41).
In obese women, but less so in men, measures of body fat distribution, of which VAT most strongly, are associated with cardiometabolic risk factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Seasonal variation in cold and light exposure may influence metabolic health.
Objective
We assessed the associations of bright sunlight and outdoor temperature with measures of ...glucose and lipid metabolism in two populations of middle-aged European subjects.
Design
Cross-sectional study.
Setting
Two population-based European cohorts.
Participants
Middle-aged nondiabetic subjects from the Oxford Biobank (OBB; N = 4327; mean age, 41.4 years) and the Netherlands Epidemiology of Obesity (NEO) study (N = 5899; mean age, 55.6 years).
Interventions
Data on outdoor bright sunlight and temperature collected from local weather stations.
Main Outcome Measures
Insulin resistance and fasting lipid levels. Multivariable regression analyses were adjusted for age, sex, percentage body fat, season, and either outdoor temperature or bright sunlight.
Results
In the OBB cohort, increased bright sunlight exposure was associated with lower fasting insulin −1.27% (95% CI, −2.09 to −0.47%) per extra hour of bright sunlight, lower homeostatic model assessment for insulin resistance (−1.36%; 95% CI, −2.23 to −0.50), lower homeostatic model assessment for β-cell function (−0.80%; 95% CI, −1.31 to −0.30), and lower triglyceride (−1.28%; 95% CI, −2.07 to −0.50) levels. In the NEO cohort generally unidirectional but weaker associations were observed. No associations between outdoor temperature and measures of glucose or lipid metabolism were detected following adjustment for bright sunlight.
Conclusions
Bright sunlight, but not outdoor temperature, might be associated with increased insulin sensitivity and lower triglyceride levels.
Outdoor temperature and sunlight were studied in relationship to cardiometabolic traits, and it was found that specifically outdoor sunlight showed beneficial associations with insulin resistance.
Scope
Mannan oligosaccharides (MOS) have proven effective at improving growth performance, while also reducing hyperlipidemia and inflammation. As atherosclerosis is accelerated both by ...hyperlipidemia and inflammation, we aim to determine the effect of dietary MOS on atherosclerosis development in hyperlipidemic ApoE*3‐Leiden.CETP (E3L.CETP) mice, a well‐established model for human‐like lipoprotein metabolism.
Methods and results
Female E3L.CETP mice were fed a high‐cholesterol diet, with or without 1% MOS for 14 weeks. MOS substantially decreased atherosclerotic lesions up to 54%, as assessed in the valve area of the aortic root. In blood, IL‐1RA, monocyte subtypes, lipids, and bile acids (BAs) were not affected by MOS. Gut microbiota composition was determined using 16S rRNA gene sequencing and MOS increased the abundance of cecal Bacteroides ovatus. MOS did not affect fecal excretion of cholesterol, but increased fecal BAs as well as butyrate in cecum as determined by gas chromatography mass spectrometry.
Conclusion
MOS decreased the onset of atherosclerosis development via lowering of plasma cholesterol levels. These effects were accompanied by increased cecal butyrate and fecal excretion of BAs, presumably mediated via interactions of MOS with the gut microbiota.
A suggested mode of action of mannan oligosaccharides (MOS) is described as follows: Dietary MOS modulate the gut microbiota in the colon, which modulate bile acid (BA) composition, leading to an increased fecal BA excretion. This is accompanied by de novo BA synthesis in the liver using plasma cholesterol as a substrate. Subsequently, the decrease in plasma cholesterol levels leads to a decrease in atherosclerosis development.
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