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

Publication ,  Journal Article
Ding, J; Reynolds, LM; Zeller, T; Müller, C; Lohman, K; Nicklas, BJ; Kritchevsky, SB; Huang, Z; de la Fuente, A; Soranzo, N; Settlage, RE ...
Published in: Diabetes
October 2015

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.

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Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

October 2015

Volume

64

Issue

10

Start / End Page

3464 / 3474

Location

United States

Related Subject Headings

  • Weight Loss
  • Transcriptome
  • Obesity
  • Male
  • Humans
  • Gene Expression Regulation
  • Gene Dosage
  • Female
  • Endocrinology & Metabolism
  • Diabetes Mellitus, Type 2
 

Citation

APA
Chicago
ICMJE
MLA
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Ding, J., Reynolds, L. M., Zeller, T., Müller, C., Lohman, K., Nicklas, B. J., … Liu, Y. (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. https://doi.org/10.2337/db14-1314
Ding, Jingzhong, Lindsay M. Reynolds, Tanja Zeller, Christian Müller, Kurt Lohman, Barbara J. Nicklas, Stephen B. Kritchevsky, et al. “Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease.Diabetes 64, no. 10 (October 2015): 3464–74. https://doi.org/10.2337/db14-1314.
Ding J, Reynolds LM, Zeller T, Müller C, Lohman K, Nicklas BJ, et al. Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease. Diabetes. 2015 Oct;64(10):3464–74.
Ding, Jingzhong, et al. “Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease.Diabetes, vol. 64, no. 10, Oct. 2015, pp. 3464–74. Pubmed, doi:10.2337/db14-1314.
Ding J, Reynolds LM, Zeller T, Müller C, Lohman K, Nicklas BJ, Kritchevsky SB, Huang Z, de la Fuente A, Soranzo N, Settlage RE, Chuang C-C, Howard T, Xu N, Goodarzi MO, Chen Y-DI, Rotter JI, Siscovick DS, Parks JS, Murphy S, Jacobs DR, Post W, Tracy RP, Wild PS, Blankenberg S, Hoeschele I, Herrington D, McCall CE, Liu Y. Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease. Diabetes. 2015 Oct;64(10):3464–3474.

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

October 2015

Volume

64

Issue

10

Start / End Page

3464 / 3474

Location

United States

Related Subject Headings

  • Weight Loss
  • Transcriptome
  • Obesity
  • Male
  • Humans
  • Gene Expression Regulation
  • Gene Dosage
  • Female
  • Endocrinology & Metabolism
  • Diabetes Mellitus, Type 2