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Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease
- Source :
- Diabetes, Ding, J; Reynolds, LM; Zeller, T; Mueller, C; Lohman, K; Nicklas, BJ; et al.(2015). Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease. DIABETES, 64(10), 3464-3474. doi: 10.2337/db14-1314. UCLA: Retrieved from: http://www.escholarship.org/uc/item/4ps239x8, DIABETES, vol 64, iss 10, Diabetes, 64(10): 3464-3474
- Publication Year :
- 2015
- Publisher :
- American Diabetes Association, 2015.
-
Abstract
- 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.
- Subjects :
- Male
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Gene regulatory network
Gene Dosage
Inflammation
Type 2 diabetes
Biology
Medical and Health Sciences
Transcriptome
Endocrinology & Metabolism
Delta-5 Fatty Acid Desaturase
Diabetes mellitus
Internal medicine
Weight Loss
Internal Medicine
medicine
Humans
Obesity
Gene
Aged
Regulation of gene expression
Aged, 80 and over
nutritional and metabolic diseases
Epigenome
medicine.disease
Endocrinology
Cholesterol
Diabetes Mellitus, Type 2
Gene Expression Regulation
Cardiovascular Diseases
lipids (amino acids, peptides, and proteins)
Female
medicine.symptom
Obesity Studies
Subjects
Details
- Language :
- English
- ISSN :
- 1939327X, 00121797, and 06500161
- Volume :
- 64
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....78c822ca42b9084f3e22a166dda78855