scholarly journals Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

2015 ◽  
Vol 29 (5) ◽  
pp. 765-776 ◽  
Author(s):  
Yipeng Sui ◽  
Robert N. Helsley ◽  
Se-Hyung Park ◽  
Xiulong Song ◽  
Zun Liu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Pregnane X Receptor ◽  
Lipid Uptake ◽  
Xenobiotic Exposure ◽  
Increased Risk ◽  
The Impact

Abstract Recent studies have associated endocrine-disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease in humans, but the underlying mechanisms responsible for these associations remain elusive. Many EDCs have been implicated in activation of the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Here we report an important role of intestinal PXR in linking xenobiotic exposure and hyperlipidemia. We identified tributyl citrate (TBC), one of a large group of Food and Drug Administration–approved plasticizers for pharmaceutical or food applications, as a potent and selective PXR agonist. TBC efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Interestingly, TBC activated intestinal PXR but did not affect hepatic PXR activity. Exposure to TBC increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. TBC-mediated PXR activation stimulated the expression of an essential cholesterol transporter, Niemann-Pick C1-like 1 (NPC1L1), in the intestine. Promoter analysis revealed a DR-4 type of PXR response element in the human NPC1L1 promoter, and TBC promoted PXR recruitment onto the NPC1L1 promoter. Consistently, TBC treatment significantly increased lipid uptake by human and murine intestinal cells and deficiency of PXR inhibited TBC-elicited lipid uptake. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating the adverse effects of EDCs on cardiovascular disease risk in humans.

scholarly journals Circadian misalignment increases cardiovascular disease risk factors in humans

2016 ◽  
Vol 113 (10) ◽  
pp. E1402-E1411 ◽  
Author(s):  
Christopher J. Morris ◽  
Taylor E. Purvis ◽  
Kun Hu ◽  
Frank A. J. L. Scheer
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Shift Work ◽  
Disease Risk ◽  
Excretion Rate ◽  
Cardiovascular Disease Risk ◽  
Circadian Misalignment ◽  
Increased Risk ◽  
The Impact

Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.

scholarly journals Consumption of dairy products and cardiovascular disease risk: results from the French prospective cohort NutriNet-Santé

2021 ◽  
pp. 1-37
Author(s):  
Laury Sellem ◽  
Bernard Srour ◽  
Kim G. Jackson ◽  
Serge Hercberg ◽  
Pilar Galan ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Dairy Products ◽  
Disease Risk ◽  
Heart Diseases ◽  
Cardiovascular Disease Risk ◽  
Dietary Intakes ◽  
Cvd Risk ◽  
Dairy Consumption ◽  
Fermented Dairy ◽  
The Impact

Abstract In France, dairy products contribute to dietary saturated fat intake, of which reduced consumption is often recommended for cardiovascular disease (CVD) prevention. Epidemiological evidence on the association between dairy consumption and CVD risk remains unclear, suggesting either null or inverse associations. This study aimed to investigate the associations between dairy consumption (overall and specific foods) and CVD risk in a large cohort of French adults. This prospective analysis included participants aged ≥ 18 years from the NutriNet-Santé cohort (2009–2019). Daily dietary intakes were collected using 24h-dietary records. Total dairy, milk, cheese, yogurts, fermented and reduced-fat dairy intakes were investigated. CVD cases (n=1,952) included cerebrovascular (n=878 cases) and coronary heart diseases (CHD, n=1,219 cases). Multivariable Cox models were performed to investigate associations. This analysis included n=104,805 French adults (mean age at baseline 42.8 years (SD 14.6)), mean follow-up 5.5 years (SD 3.0, i.e. 579,155 persons years). There were no significant associations between dairy intakes and total CVD or CHD risks. However, the consumption of at least 160 g/d of fermented dairy (e.g. cheese and yogurts) was associated with a reduced risk of cerebrovascular diseases compared to intakes below 57 g/d (HR=0.81 [0.66-0.98], p-trend=0.01). Despite being a major dietary source of saturated fats, dairy consumption was not associated with CVD or CHD risks in this study. However, fermented dairy was associated with a lower cerebrovascular disease risk. Robust randomized controlled trials are needed to further assess the impact of consuming different dairy foods on CVD risk and potential underlying mechanisms.

scholarly journals Large-Scale Analysis of Apolipoprotein CIII Glycosylation by Ultrahigh Resolution Mass Spectrometry

2021 ◽  
Vol 9 ◽  
Author(s):  
Daniel Demus ◽  
Annemieke Naber ◽  
Viktoria Dotz ◽  
Bas C. Jansen ◽  
Marco R. Bladergroen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Lipid Metabolism ◽  
Large Scale ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Sinapinic Acid ◽  
Chemical Oxidation ◽  
Ultrahigh Resolution ◽  
Apolipoprotein Ciii

Apolipoprotein-CIII (apo-CIII) is a glycoprotein involved in lipid metabolism and its levels are associated with cardiovascular disease risk. Apo-CIII sialylation is associated with improved plasma triglyceride levels and its glycosylation may have an effect on the clearance of triglyceride-rich lipoproteins by directing these particles to different metabolic pathways. Large-scale sample cohort studies are required to fully elucidate the role of apo-CIII glycosylation in lipid metabolism and associated cardiovascular disease. In this study, we revisited a high-throughput workflow for the analysis of intact apo-CIII by ultrahigh-resolution MALDI FT-ICR MS. The workflow includes a chemical oxidation step to reduce methionine oxidation heterogeneity and spectrum complexity. Sinapinic acid matrix was used to minimize the loss of sialic acids upon MALDI. MassyTools software was used to standardize and automate MS data processing and quality control. This method was applied on 771 plasma samples from individuals without diabetes allowing for an evaluation of the expression levels of apo-CIII glycoforms against a panel of lipid biomarkers demonstrating the validity of the method. Our study supports the hypothesis that triglyceride clearance may be regulated, or at least strongly influenced by apo-CIII sialylation. Interestingly, the association of apo-CIII glycoforms with triglyceride levels was found to be largely independent of body mass index. Due to its precision and throughput, the new workflow will allow studying the role of apo-CIII in the regulation of lipid metabolism in various disease settings.

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