Epigenetic Alterations in Human Liver From Subjects With Type 2 Diabetes in Parallel With Reduced Folate Levels

Nilsson, Erika; Matte, Ashok; Perfilyev, Alexander; Mello, Vanessa D. de; Käkelä, Pirjo; Pihlajamäki, Jussi; Ling, Charlotte

doi:10.1210/jc.2015-3204

Cited by 159 publications

(167 citation statements)

References 60 publications

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“…DNMT1 expression was measured in the HumanHT-12 Expression BeadChip array (Illumina) and remained after pre-processing and filtering of the data. 18 The liver DNMT1 expression was »5% higher in individuals with NASH compared with individuals with simple steatosis or normal liver (7.1 § 0.5 vs. 6.7 § 0.5; P D 0.007 in models adjusted for BMI, age, sex, and T2D). …”

Section: Global Methylation In Liver Estimated By Line-1 Methylation mentioning

confidence: 89%

“…18,33,53 Ninety-five individuals who were accepted for the Roux-en-Y gastric bypass (RYGB) operation, were selected for this study from the KOBS cohort to obtain balance study groups with normal liver steatosis, simple steatosis and NASH (see below histological analysis).…”

Section: Study Participants and Analyses Of Clinical And Metabolic Pamentioning

confidence: 99%

“…18,56 The raw methylation data in b-values were converted to M-values {M D log2 [b/(1-b)]}, which were then used for data normalization, to correct for probe design bias and batch effects as well as statistical tests, as described previously. 18 To easier interpret the results, M-values were reconverted to b-values, which were used when describing the data and creating figures. A total of 455,526 CpG sites were studied for DNA methylation differences associated with liver phenotypes.…”

Section: Gw Analysis Of Dna Methylation In Human Livermentioning

confidence: 99%

“…Since we have earlier published results related to differential DNA methylation and T2D, 18 we now carefully adjusted our analyses for T2D. To identify differences in DNA methylation and mRNA expression in the liver associated with NASH and steatosis, a linear regression model was used including T2D, gender, BMI, and age as covariates and DNA methylation or mRNA expression as the dependent variable.…”

Section: Statistical Analysesmentioning

confidence: 99%

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

et al. 2017

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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 2 , 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 D 0.0036) and cancer (q D 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 D ¡0.45, P D 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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Section: Global Methylation In Liver Estimated By Line-1 Methylation mentioning

confidence: 89%

Section: Study Participants and Analyses Of Clinical And Metabolic Pamentioning

confidence: 99%

Section: Gw Analysis Of Dna Methylation In Human Livermentioning

confidence: 99%

Section: Statistical Analysesmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2017

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“…Likewise, coordinated epigenetic changes may also improve metabolic health after therapeutic intervention. Systematic studies of the DNA methylation landscape and the related transcriptome of metabolic tissues from obese and/or type 2 diabetic patients show that DNA methylation is altered in metabolic diseases [4,24,26,32,33,35,36,40,43,46,47]. For example DNA methylation at the HIF3A loci in blood cells is correlated with BMI in Caucasian adults [13].…”

Section: Introductionmentioning

confidence: 99%

Altered DNA methylation of glycolytic and lipogenic genes in liver of obese and type 2 diabetic patients

Kirchner

Sinha

Näslund

et al. 2015

Exp Clin Endocrinol Diabetes

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Objective: Epigenetic modifications contribute to the etiology of type 2 diabetes. Method: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing. Result: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.

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Dual epigenetic changes in diabetes mellitus‐associated pancreatic ductal adenocarcinoma correlate with downregulation of E‐cadherin and worsened prognosis

Hara

Mizukami

Yamazaki

et al. 2023

The Journal of Pathology CR

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Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR‐100‐5p is known to be changed in DM patients and can suppress the expression of E‐cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E‐cadherin and nuclear β‐catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin‐fixed paraffin‐embedded tissue sections. TaqMan miR assays were applied to assess miR‐100‐5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation‐specific polymerase chain reaction. Immunohistochemistry revealed that decreased E‐cadherin expression and increased nuclear β‐catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long‐duration DM (≥3 years) was a significant factor contributing to CDH1 promoter methylation (p < 0.01), while miR‐100‐5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR‐100‐5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR‐100‐5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease‐free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis.

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Epigenetic Alterations in Human Liver From Subjects With Type 2 Diabetes in Parallel With Reduced Folate Levels

Abstract: Our study highlights the importance of epigenetic and transcriptional changes in the liver from subjects with T2D. Reduced circulating folate levels may provide an explanation for hypomethylation in the human diabetic liver.

Cited by 159 publications

References 60 publications

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

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

Altered DNA methylation of glycolytic and lipogenic genes in liver of obese and type 2 diabetic patients

Dual epigenetic changes in diabetes mellitus‐associated pancreatic ductal adenocarcinoma correlate with downregulation of E‐cadherin and worsened prognosis

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