Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease.
Tina Rönn, Alexander Perfilyev, Josefine Jönsson, Karl-Fredrik Eriksson, Sine W Jørgensen, Charlotte Brøns, Linn Gillberg, Allan Vaag, Elisabet Stener-Victorin, Charlotte Ling
Author Information
Tina Rönn: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, 205 02 Malmö, Sweden. ORCID
Alexander Perfilyev: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, 205 02 Malmö, Sweden.
Josefine Jönsson: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, 205 02 Malmö, Sweden.
Karl-Fredrik Eriksson: Department of Clinical Sciences, Vascular Diseases, Lund University, 205 02 Malmö, Sweden.
Sine W Jørgensen: Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.
Charlotte Brøns: Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.
Linn Gillberg: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Allan Vaag: Steno Diabetes Center Copenhagen, DK-2820, Gentofte, Denmark.
Elisabet Stener-Victorin: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Charlotte Ling: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, 205 02 Malmö, Sweden.
Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue. DNA methylation and gene expression were analysed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, low-density lipoprotein, high-density lipoprotein and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance. We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2 and HOXA5 in the male cohort (P ≤ 1.1 × 10-7), and 63 associations, e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance. This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.
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