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.
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Reynolds
authors.affiliation: University Heart Center Hamburg, Clinic for General and Interventional Cardiology, and DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: University Heart Center Hamburg, Clinic for General and Interventional Cardiology, and DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Nicklas
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Kritchevsky
authors.affiliation: Duke University, Durham, NC.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Biomathematics and Bioinformatics, Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
authors.forename: Alberto
authors.initials: A
authors.lastname: de la Fuente
authors.affiliation: CRS4 Bioinformatica, Pula, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Settlage
authors.affiliation: Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chuang
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Timothy
authors.initials: T
authors.lastname: Howard
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Y-D Ida
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: The New York Academy of Medicine, New York, NY.
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.affiliation: Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: Duke University, Durham, NC.
authors.forename: Susan
authors.initials: S
authors.lastname: Murphy
authors.affiliation: School of Public Health, University of Minnesota, Minneapolis, MN.
authors.forename: David R
authors.initials: DR
authors.lastname: Jacobs
authors.affiliation: Johns Hopkins University, Baltimore, MD.
authors.forename: Wendy
authors.initials: W
authors.lastname: Post
authors.affiliation: University of Vermont, Colchester, VT.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.affiliation: Center for Thrombosis and Hemostasis and Department of Medicine 2, University Medical Center of the Johannes Gutenberg University Mainz, and DZHK (German Centre for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.affiliation: University Heart Center Hamburg, Clinic for General and Interventional Cardiology, and DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA.
authors.forename: Ina
authors.initials: I
authors.lastname: Hoeschele
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: David
authors.initials: D
authors.lastname: Herrington
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
authors.affiliation: Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC yoliu@wakehealth.edu.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism*; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D009765:Obesity / Q000150:complications*; D059467:Transcriptome; D015431:Weight Loss / Q000502:physiology
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D002784:Cholesterol; C000716847:FADS1 protein, human