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

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Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease. / Ding, Jingzhong; Reynolds, Lindsay M; Zeller, Tanja; Müller, Christian; Lohman, Kurt; Nicklas, Barbara J; Kritchevsky, Stephen B; Huang, Zhiqing; de la Fuente, Alberto; Soranzo, Nicola; Settlage, Robert E; Chuang, Chia-Chi; Howard, Timothy; Xu, Ning; Goodarzi, Mark O; Chen, Y-D Ida; Rotter, Jerome I; Siscovick, David S; Parks, John S; Murphy, Susan; Jacobs, David R; Post, Wendy; Tracy, Russell P; Wild, Philipp S; Blankenberg, Stefan; Hoeschele, Ina; Herrington, David; McCall, Charles E; Liu, Yongmei.

in: DIABETES, Jahrgang 64, Nr. 10, 10.2015, S. 3464-3474.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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 2015, 'Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease', DIABETES, Jg. 64, Nr. 10, S. 3464-3474. https://doi.org/10.2337/db14-1314

APA

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

Vancouver

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 Okt;64(10):3464-3474. https://doi.org/10.2337/db14-1314

Bibtex

@article{853e2a0b4ae34e9b9c6726ad3d5b89ea,
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. ",
keywords = "Aged, Aged, 80 and over, Cardiovascular Diseases/etiology, Cholesterol/metabolism, Diabetes Mellitus, Type 2/etiology, Female, Gene Dosage, Gene Expression Regulation, Humans, Male, Obesity/complications, Transcriptome, Weight Loss/physiology",
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 Chia-Chi Chuang 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",
note = "{\textcopyright} 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.",
year = "2015",
month = oct,
doi = "10.2337/db14-1314",
language = "English",
volume = "64",
pages = "3464--3474",
journal = "DIABETES",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "10",

}

RIS

TY - JOUR

T1 - Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease

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

N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Cardiovascular Diseases/etiology

KW - Cholesterol/metabolism

KW - Diabetes Mellitus, Type 2/etiology

KW - Female

KW - Gene Dosage

KW - Gene Expression Regulation

KW - Humans

KW - Male

KW - Obesity/complications

KW - Transcriptome

KW - Weight Loss/physiology

U2 - 10.2337/db14-1314

DO - 10.2337/db14-1314

M3 - SCORING: Journal article

C2 - 26153245

VL - 64

SP - 3464

EP - 3474

JO - DIABETES

JF - DIABETES

SN - 0012-1797

IS - 10

ER -