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Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease

Rönn, Tina LU ; Perfilyev, Alexander LU orcid ; Jönsson, Josefine LU orcid ; Eriksson, Karl-Fredrik LU ; Jørgensen, Sine W ; Brøns, Charlotte LU ; Gillberg, Linn LU ; Vaag, Allan LU ; Stener-Victorin, Elisabet and Ling, Charlotte LU orcid (2023) In Human Molecular Genetics 32(11). p.1875-1887
Abstract

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... (More)

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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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Male, Female, DNA Methylation/genetics, Triglycerides/genetics, Insulin Resistance/genetics, Epigenesis, Genetic/genetics, Adipose Tissue/metabolism
in
Human Molecular Genetics
volume
32
issue
11
pages
1875 - 1887
publisher
Oxford University Press
external identifiers
  • scopus:85169104688
  • pmid:36752523
ISSN
0964-6906
DOI
10.1093/hmg/ddad024
language
English
LU publication?
yes
additional info
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
id
436cb686-1d84-4d53-a1e4-14d81ca4fff3
date added to LUP
2023-08-31 08:26:18
date last changed
2025-01-27 15:09:32
@article{436cb686-1d84-4d53-a1e4-14d81ca4fff3,
  abstract     = {{<p>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.</p>}},
  author       = {{Rönn, Tina and Perfilyev, Alexander and Jönsson, Josefine and Eriksson, Karl-Fredrik and Jørgensen, Sine W and Brøns, Charlotte and Gillberg, Linn and Vaag, Allan and Stener-Victorin, Elisabet and Ling, Charlotte}},
  issn         = {{0964-6906}},
  keywords     = {{Humans; Male; Female; DNA Methylation/genetics; Triglycerides/genetics; Insulin Resistance/genetics; Epigenesis, Genetic/genetics; Adipose Tissue/metabolism}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{11}},
  pages        = {{1875--1887}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddad024}},
  doi          = {{10.1093/hmg/ddad024}},
  volume       = {{32}},
  year         = {{2023}},
}