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An integrative multiomic network model links the canonical lipid metabolism pathway to glucose regulation in coronary artery disease

ABSTRACT: Elevated plasma cholesterol and Type 2 Diabetes (T2D) are associated with Coronary Artery Disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explored the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic and clinical data, we identified a Glucose and Lipid Determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impacted lipid and glucose levels in inverse directions. Experimental knockdown of one of the GLD network master regulators, Lanosterol Synthase (LSS), in mouse confirmed the inverse relationships to glucose and lipid levels as predicted by our model and provided mechanistic insights.

ORGANISM(S): Mus musculus

PROVIDER: GSE157223 | GEO | 2020/09/01

REPOSITORIES: GEO

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Project description:Rationale: Epicardial adipose tissue (EAT) has been independently associated with non-calcified, high-risk coronary plaques in low-to intermediate risk subjects. Recently, a bidirectional communication was shown between EAT and diseased coronary arteries. In high-risk patients it is unknown whether quantitative measures of EAT can capture, and which molecular players are involved in this mutual interplay. Objective: In a high-risk population, we aimed to determine how the volume of EAT is linked to coronary artery disease (CAD) and to identify potential EAT-deregulated pathways in CAD patients specifically related to coronary artery calcification (CAC). Methods and Results: In a prospective cohort of 574 degenerative severe aortic stenosis patients referred to cardiac surgery, we quantified fat depots by computed tomography (CT) and performed a comparative quantitative proteomics of thoracic fat, including EAT, mediastinal (MAT) and subcutaneous (SAT) adipose tissues. We did not find an independent association of EAT volume with the severity, distribution and complexity of coronary stenosis in invasive coronary angiography. Although, EAT volume was correlated with high CAC, its cardiovascular risk factors-adjusted association was not significant. Taking as reference non-CAD matched-patients and compared to MAT and SAT, EAT proteomic signature of CAD was characterized by up-regulation of pro-calcifying annexins (Annexin A2, ANXA2), fatty acid binding transporters (FABP4) and inflammatory signaling proteins, and by down-regulation of fetuin-A and redox state regulatory enzymes. In EAT, ANXA2 regulation was positively correlated with CAC. EAT gene expression studies confirmed overexpression of ANXA2 and FABP4 in CAD, but no expression of FETUA was detected. Compared with non-CAD, fetuin-A circulating levels were higher in CAD, whereas no fetuin-A pericardial fluid differences were found. Conclusions: In this high-risk cohort, EAT presented an imbalance of pro-calcifying, pro-inflammatory and lipid transporters mediators. These local EAT-mediated regulatory mechanisms were not reflected by the CT volume of EAT alone.

Project description:The biological functions of epicardial adipose tissue (EAT) remain largely elusive. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). Objectives of this study were to identify genes that are up- or down-regulated among three adipose tissues (AT), namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases. Samples were collected from patients undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in all three AT depots of six men using the lllumina® HumanWG-6 v3.0 expression BeadChips. Twenty-two and 73 genes were up-regulated in EAT compared to mediastinal and subcutaneous AT, respectively. Ninety-four genes were down-regulated in EAT compared to subcutaneous adipose depot. However, none were significantly down-regulated in EAT compared to mediastinal fat. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (epicardial > mediastinal > subcutaneous). The results of ADORA1 and PTGDS were confirmed by qPCR in 25 biological replicates. Overall, the transcriptional profiles of EAT and MAT were similar compared to the subcutaneous compartment. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD. Samples of epicardial, mediastinal and subscutaneous adipose tissue were collected from the chest of 6 male patients undergoing coronary artery bypass grafting surgeries. The RNA was labeled and hybridized using a standard Illumina protocol (https://icom.illumina.com/Login?ReturnUrl=%2ficom%2fsoftware.ilmn%3fid%3d214&id=214). Three pairwise comparison among the three adipose tissue were made using significance analysis of microarrays.

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An integrative multiomic network model links the canonical lipid metabolism pathway to glucose regulation in coronary artery disease

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