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Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

de Mello, Vanessa; Matte, Ashok; Perfilyev, Alexander LU ; Männistö, Ville; Rönn, Tina LU ; Nilsson, Emma LU ; Käkelä, Pirjo; Ling, Charlotte LU and Pihlajamäki, Jussi (2017) In Epigenetics 12(4). p.287-295
Abstract

Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m2, type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA... (More)

Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m2, type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q < 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q = 0.0036) and cancer (q = 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB (r = −0.45, P = 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA methylation, insulin action, liver epigenetics, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis
in
Epigenetics
volume
12
issue
4
pages
9 pages
publisher
Landes Bioscience
external identifiers
  • scopus:85016487266
  • wos:000399567600005
ISSN
1559-2294
DOI
10.1080/15592294.2017.1294305
language
English
LU publication?
yes
id
eff5cca5-68df-4194-80c5-ccffdda38246
date added to LUP
2017-04-12 13:45:41
date last changed
2017-09-18 13:32:22
@article{eff5cca5-68df-4194-80c5-ccffdda38246,
  abstract     = {<p>Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m<sup>2</sup>, type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q &lt; 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q = 0.0036) and cancer (q = 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB (r = −0.45, P = 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.</p>},
  author       = {de Mello, Vanessa and Matte, Ashok and Perfilyev, Alexander and Männistö, Ville and Rönn, Tina and Nilsson, Emma and Käkelä, Pirjo and Ling, Charlotte and Pihlajamäki, Jussi},
  issn         = {1559-2294},
  keyword      = {DNA methylation,insulin action,liver epigenetics,non-alcoholic fatty liver disease,non-alcoholic steatohepatitis},
  language     = {eng},
  month        = {03},
  number       = {4},
  pages        = {287--295},
  publisher    = {Landes Bioscience},
  series       = {Epigenetics},
  title        = {Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action},
  url          = {http://dx.doi.org/10.1080/15592294.2017.1294305},
  volume       = {12},
  year         = {2017},
}