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

• DOI: 10.2337/db14-1314
• Publication Date: 2015-07-08T02:32:54Z
• Authors: Jingzhong Ding; Lindsay M. Reynolds; Tanja Zeller; Christian Müller; Kurt Lohman; Barbara J. Nicklas; Stephen B. Kritch...; 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 Murphy; David R. Jacobs; Wendy Post; Russell P. Tracy; Philipp S. Wild; Stefan Blankenberg; Ina Hoeschele; David Herrington; Charles E. McCall; Yongmei Liu
• Keywords: ABCG1

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