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

Author:
  • Vanessa de Mello
  • Ashok Matte
  • Alexander Perfilyev
  • Ville Männistö
  • Tina Rönn
  • Emma Nilsson
  • Pirjo Käkelä
  • Charlotte Ling
  • Jussi Pihlajamäki
Publishing year: 2017-03-29
Language: English
Pages: 287-295
Publication/Series: Epigenetics
Volume: 12
Issue: 4
Document type: Journal article
Publisher: Landes Bioscience

Abstract english

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.

Keywords

  • Medical Genetics
  • Gastroenterology and Hepatology
  • DNA methylation
  • insulin action
  • liver epigenetics
  • non-alcoholic fatty liver disease
  • non-alcoholic steatohepatitis

Other

Published
  • Epigenetics and Diabetes
  • ISSN: 1559-2294
Tina Rönn
E-mail: tina.ronn [at] med.lu.se

Assistant researcher

Epigenetics and Diabetes

+46 40 39 12 18

CRC 91-12-021

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00