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RESEARCH PRODUCT

Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease

Stefan BlankenbergRussell P. TracyY.-d. Ida ChenRobert E. SettlageBarbara J. NicklasNing XuIna HoescheleZhiqing HuangStephen B. KritchevskyKurt LohmanMark O. GoodarziCharles E. MccallTanja ZellerAlberto De La FuenteTimothy D. HowardNicola SoranzoLindsay M. ReynoldsJerome I. RotterChristian MüllerDavid M. HerringtonYongmei LiuJingzhong DingChia-chi ChuangSusan K. MurphyWendy PostDavid SiscovickJohn S. ParksDavid R. JacobsPhilipp S. Wild

subject

Malemedicine.medical_specialtyEndocrinology Diabetes and MetabolismGene regulatory networkGene DosageInflammationType 2 diabetesBiologyMedical and Health SciencesTranscriptomeEndocrinology & MetabolismDelta-5 Fatty Acid DesaturaseDiabetes mellitusInternal medicineWeight LossInternal MedicinemedicineHumansObesityGeneAgedRegulation of gene expressionAged 80 and overnutritional and metabolic diseasesEpigenomemedicine.diseaseEndocrinologyCholesterolDiabetes Mellitus Type 2Gene Expression RegulationCardiovascular Diseaseslipids (amino acids peptides and proteins)Femalemedicine.symptomTranscriptomeObesity Studies

description

Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.

yearjournalcountryeditionlanguage
2015-10-01Diabetes
10.2337/db14-1314http://europepmc.org/articles/PMC4587646