Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

The present study is the first intervention study in a well-established, translational mouse model for hyperlipidaemia and atherosclerosis showing that anacetrapib dose-dependently reduces atherosclerosis development and adds to the anti-atherogenic effects of atorvastatin. This effect is mainly ascribed to the reduction in non-HDL-C despite a remarkable increase in HDL-C and without affecting HDL functionality. In addition, anacetrapib improves lesion stabilit

Common variants associated with OSMR expression contribute to carotid plaque vulnerability, but not to cardiovascular disease in humans

This dataset pertains to the data used for the article "van Keulen D et al. Common variants associated with OSMR expression contribute to carotid plaque vulnerability, but not to cardiovascular disease in humans. 2021"; below the abstract. Background and aims Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility. Methods and results We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression. We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β=0.118 ± s.e.=0.040, p=3.00×10-3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β=0.248 ± s.e.=0.088, p=4.66×10-3, C allele) and collagen content (β=-0.259 ± s.e.=0.095, p=6.22×10-3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus. Conclusions Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility. Competing Interest Statement DvK is employed by Quorics B.V., and DT is employed by SkylineDx B.V and Quorics B.V. Quorics B.V. and SkylineDx B.V. had no part whatsoever in the conception, design, or execution of this study, nor the preparation and contents of this manuscript. Scripts Scripts are posted at GitHub https://github.com/swvanderlaan/2019_vankeulen_d_osmr

Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health

Perfluoroalkyl Sulfonates Cause Alkyl Chain Length–Dependent Hepatic Steatosis and Hypolipidemia Mainly by Impairing Lipoprotein Production in APOE*3-Leiden CETP Mice

Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) are stable perfluoroalkyl sulfonate (PFAS) surfactants, and PFHxS and PFOS are frequently detected in human biomonitoring studies. Some epidemiological studies have shown modest positive correlations of serum PFOS with non-high-density lipoprotein (HDL)-cholesterol (C). This study investigated the mechanism underlying the effect of PFAS surfactants on lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Westerntype diet with PFBS, PFHxS, or PFOS (30, 6, and 3 mg/kg/day, respectively) for 4-6 weeks. Whereas PFBS modestly reduced only plasma triglycerides (TG), PFHxS and PFOS markedly reduced TG, non-HDL-C, and HDL-C. The decrease in very lowdensity lipoprotein (VLDL) was caused by enhanced lipoprotein lipase-mediated VLDL-TG clearance and by decreased production of VLDL-TG and VLDL-apolipoprotein B. Reduced HDL production, related to decreased apolipoprotein AI synthesis, resulted in decreased HDL. PFHxS and PFOS increased liver weight and hepatic TG content. Hepatic gene expression profiling data indicated that these effects were the combined result of peroxisome proliferator-activated receptor alpha and pregnane X receptor activation. In conclusion, the potency of PFAS to affect lipoprotein metabolism increased with increasing alkyl chain length. PFHxS and PFOS reduce plasma TG and total cholesterol mainly by impairing lipoprotein production, implying that the reported positive correlations of serum PFOS and non-HDL-C are associative rather than causal. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved