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 Murphy; David R. Jacobs; Wendy Post; Russell P. Tracy; Philipp S. Wild; Stefan Blankenberg; Ina Hoeschele; David Herrington; Charles E. McCall; Yongmei Liu

doi:10.2337/db14-1314

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

Epidemiology & Community Health

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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 language	English (US)
Pages (from-to)	3464-3474
Number of pages	11
Journal	Diabetes
Volume	64
Issue number	10
DOIs	https://doi.org/10.2337/db14-1314
State	Published - Oct 2015

Bibliographical note

Publisher Copyright:
© 2015 by the American Diabetes Association.

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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

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, CC, Howard, T, Xu, N, Goodarzi, MO, Chen, YDI, 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 2015, '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, pp. 3464-3474. https://doi.org/10.2337/db14-1314

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

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.",

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

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AU - Ding, Jingzhong

AU - Reynolds, Lindsay M.

AU - Zeller, Tanja

AU - Müller, Christian

AU - Lohman, Kurt

AU - Nicklas, Barbara J.

AU - Kritchevsky, Stephen B.

AU - Huang, Zhiqing

AU - De La Fuente, Alberto

AU - Soranzo, Nicola

AU - Settlage, Robert E.

AU - Chuang, Chia Chi

AU - Howard, Timothy

AU - Xu, Ning

AU - Goodarzi, Mark O.

AU - Chen, Y. D Ida

AU - Rotter, Jerome I.

AU - Siscovick, David S.

AU - Parks, John S.

AU - Murphy, Susan

AU - Jacobs, David R.

AU - Post, Wendy

AU - Tracy, Russell P.

AU - Wild, Philipp S.

AU - Blankenberg, Stefan

AU - Hoeschele, Ina

AU - Herrington, David

AU - McCall, Charles E.

AU - Liu, Yongmei

PY - 2015/10

Y1 - 2015/10

N2 - 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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Alterations of a cellular cholesterol metabolism network are a molecular feature of obesity-related type 2 diabetes and cardiovascular disease

Abstract

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