Alterations of a cellular cholesterol metabolism network are a molecular feature of obesity-related type 2 diabetes and cardiovascular disease

Jingzhong Ding, Lindsay M. Reynolds, Tanja Zeller, Christian Müller, Kurt Lohman, Barbara J. Nicklas, Stephen B. Kritchevsky, Zhiqing Huang, Alberto De La Fuente, Nicola Soranzo, Robert E. Settlage, Chia Chi Chuang, Timothy Howard, Ning Xu, Mark O. Goodarzi, Y. D.Ida Chen, Jerome I. Rotter, David S. Siscovick, John S. Parks, Susan MurphyDavid R. Jacobs, Wendy Post, Russell P. Tracy, Philipp S. Wild, Stefan Blankenberg, Ina Hoeschele, David Herrington, Charles E. McCall, Yongmei Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3464-3474
Number of pages11
JournalDiabetes
Volume64
Issue number10
DOIs
StatePublished - Oct 2015

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ding, J., Reynolds, L. M., Zeller, T., Müller, C., Lohman, K., Nicklas, B. J., Kritchevsky, S. B., Huang, Z., De La Fuente, A., Soranzo, N., Settlage, R. E., Chuang, C. C., Howard, T., Xu, N., Goodarzi, M. O., Chen, Y. D. I., Rotter, J. I., Siscovick, D. S., Parks, J. S., ... 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