Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits

Erratum for Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. [BMC Med Genomics. 2019

ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

International audienceBACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-)Apob(100/100)). CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome

Moving to capture children’s attention: developing a methodology for measuring visuomotor attention

Attention underpins many activities integral to a child’s development. However, methodological limitations currently make large-scale assessment of children’s attentional skill impractical, costly and lacking in ecological validity. Consequently we developed a measure of ‘Visual Motor Attention’ (VMA) - a construct defined as the ability to sustain and adapt visuomotor behaviour in response to task-relevant visual information. In a series of experiments, we evaluated the capability of our method to measure attentional processes and their contributions in guiding visuomotor behaviour. Experiment 1 established the method’s core features (ability to track stimuli moving on a tablet-computer screen with a hand-held stylus) and demonstrated its sensitivity to principled manipulations in adults’ attentional load. Experiment 2 standardised a format suitable for use with children and showed construct validity by capturing developmental changes in executive attention processes. Experiment 3 tested the hypothesis that children with and without coordination difficulties would show qualitatively different response patterns, finding an interaction between the cognitive and motor factors underpinning responses. Experiment 4 identified associations between VMA performance and existing standardised attention assessments and thereby confirmed convergent validity. These results establish a novel approach to measuring childhood attention that can produce meaningful functional assessments that capture how attention operates in an ecologically valid context (i.e. attention's specific contribution to visuomanual action)

Plasma Cholesterol-Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (>= 80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob(100/100)Mttp(flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions. Author Summary The main underlying cause of heart attacks and strokes is atherosclerosis. One strategy to prevent these often deadly clinical events is therefore either to slow atherosclerosis progression or better, induce regression of atherosclerotic plaques making them more stable. Plasma cholesterol lowering (PCL) is the most efficient way to induce atherosclerosis regression but sometimes fails to do so. In our study, we used a mouse model with elevated LDL cholesterol levels, similar to humans who develop early atherosclerosis, and a genetic switch to lower plasma cholesterol at any time during atherosclerosis progression. In this model, we examined atherosclerosis gene expression and regression in response to PCL at three different stages of atherosclerosis progression. PCL led to complete regression in mice with early lesions but was incomplete in mice with mature and advanced lesions, indicating that early prevention with PCL in individuals with increased risk for heart attack or stroke would be particularly useful. In addition, by inferring PCL-responsive gene networks in early, mature and advanced atherosclerotic lesions, we identified key drivers specific for regression of early (PPARG), mature (MLL5) and advanced (SRSF10/XRN2) atherosclerosis. These key drivers should be interesting therapeutic targets to enhance PCL-mediated regression of atherosclerosis

Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor delta

Activators of peroxisome proliferator-activated receptor (PPAR)γ have been studied intensively for their insulin-sensitizing properties and antidiabetic effects. Recently, a specific PPARδ activator (GW501516) was reported to attenuate plasma glucose and insulin levels when administered to genetically obese ob/ob mice. This study was performed to determine whether specific activation of PPARδ has direct effects on insulin action in skeletal muscle. Specific activation of PPARδ using two pharmacological agonists (GW501516 and GW0742) increased glucose uptake independently of insulin in differentiated C2C12 myotubes. In cultured primary human skeletal myotubes, GW501516 increased glucose uptake independently of insulin and enhanced subsequent insulin stimulation. PPARδ agonists increased the respective phosphorylation and expression of AMP-activated protein kinase 1.9 fold (P < 0.05) and 1.8 fold (P < 0.05), of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) 2.2-fold (P < 0.05) and 1.7-fold (P < 0.05), and of p38 MAPK 1.2-fold (P < 0.05) and 1.4-fold (P < 0.05). Basal and insulin-stimulated protein kinase B/Akt was unaltered in cells pre-exposed to PPARδ agonists. Preincubation of myotubes with the p38 MAPK inhibitor SB203580 reduced insulin- and PPARδ-mediated increase in glucose uptake, whereas the mitogen-activated protein kinase kinase inhibitor PD98059 was without effect. PPARδ agonists reduced mRNA expression of PPARδ, sterol regulatory element binding protein (SREBP)-1a, and SREBP-1c (P < 0.05). In contrast, mRNA expression of PPARγ, PPARγ coactivator 1, GLUT1, and GLUT4 was unaltered. Our results provide evidence to suggest that PPARδ agonists increase glucose metabolism and promote gene regulatory responses in cultured human skeletal muscle. Moreover, we provide biological validation of PPARδ as a potential target for antidiabetic therapy

Plaque Evaluation by Ultrasound and Transcriptomics Reveals BCLAF1 as a Regulator of Smooth Muscle Cell Lipid Transdifferentiation in Atherosclerosis

Background: Understanding the processes behind carotid plaque instability is necessary to develop methods for identification of patients and lesions with stroke risk. Here, we investigated molecular signatures in human plaques stratified by echogenicity as assessed by duplex ultrasound. Methods: Lesion echogenicity was correlated to microarray gene expression profiles from carotid endarterectomies (n=96). The findings were extended into studies of human and mouse atherosclerotic lesions in situ, followed by functional investigations in vitro in human carotid smooth muscle cells (SMCs). Results: Pathway analyses highlighted muscle differentiation, iron homeostasis, calcification, matrix organization, cell survival balance, and BCLAF1 (BCL2 [B-cell lymphoma 2]-associated transcription factor 1) as the most significant signatures. BCLAF1 was downregulated in echolucent plaques, positively correlated to proliferation and negatively to apoptosis. By immunohistochemistry, BCLAF1 was found in normal medial SMCs. It was repressed early during atherogenesis but reappeared in CD68+ cells in advanced plaques and interacted with BCL2 by proximity ligation assay. In cultured SMCs, BCLAF1 was induced by differentiation factors and mitogens and suppressed by macrophage-conditioned medium. BCLAF1 silencing led to downregulation of BCL2 and SMC markers, reduced proliferation, and increased apoptosis. Transdifferentiation of SMCs by oxLDL (oxidized low-denisty lipoprotein) was accompanied by upregulation of BCLAF1, CD36, and CD68, while oxLDL exposure with BCLAF1 silencing preserved MYH (myosin heavy chain) 11 expression and prevented transdifferentiation. BCLAF1 was associated with expression of cell differentiation, contractility, viability, and inflammatory genes, as well as the scavenger receptors CD36 and CD68. BCLAF1 expression in CD68+/BCL2+ cells of SMC origin was verified in plaques from MYH11 lineage-tracing atherosclerotic mice. Moreover, BCLAF1 downregulation associated with vulnerability parameters and cardiovascular risk in patients with carotid atherosclerosis. Conclusions: Plaque echogenicity correlated with enrichment of distinct molecular pathways and identified BCLAF1, previously not described in atherosclerosis, as the most significant gene. Functionally, BCLAF1 seems necessary for survival and transdifferentiation of SMCs into a macrophage-like phenotype. The role of BCLAF1 in plaque vulnerability should be further evaluated.Vascular Surger