title: Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action.
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 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.
authors.affiliation: a Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland , Kuopio , Finland.
authors.forename: Vanessa D
authors.initials: VD
authors.lastname: de Mello
authors.affiliation: a Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland , Kuopio , Finland.
authors.forename: Ashok
authors.initials: A
authors.lastname: Matte
authors.affiliation: b Epigenetics and Diabetes Unit, Department of Clinical Sciences , Lund University Diabetes Centre , Malmö , Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Perfilyev
authors.affiliation: a Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland , Kuopio , Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Männistö
authors.affiliation: b Epigenetics and Diabetes Unit, Department of Clinical Sciences , Lund University Diabetes Centre , Malmö , Sweden.
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.affiliation: b Epigenetics and Diabetes Unit, Department of Clinical Sciences , Lund University Diabetes Centre , Malmö , Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: c Department of Surgery , University of Eastern Finland and Kuopio University Hospital , Kuopio , Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Käkelä
authors.affiliation: b Epigenetics and Diabetes Unit, Department of Clinical Sciences , Lund University Diabetes Centre , Malmö , Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
authors.affiliation: a Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland , Kuopio , Finland.|d Clinical Nutrition and Obesity Center , Kuopio University Hospital , Kuopio , Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
mesh_terms: D000328:Adult; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*
chemical_list: D007328:Insulin
keywords: DNA methylation; insulin action; liver epigenetics; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis