Altered DNA Methylation of Glycolytic and Lipogenic Genes in Liver from Obese and Type 2 Diabetic Patients

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2016 Mar 16

PMID 26977391

Citations 66

Authors

Henriette Kirchner

Indranil Sinha

Hui Gao

Maxwell A Ruby

Milena Schonke

Jessica M Lindvall

Romain Barres

Anna Krook

Erik Naslund

Karin Dahlman-Wright

Juleen R Zierath

Affiliations

Soon will be listed here.

Abstract

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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References

Jornayvaz F, Shulman G . Diacylglycerol activation of protein kinase Cε and hepatic insulin resistance. Cell Metab. 2012; 15(5):574-84. PMC: 3353749. DOI: 10.1016/j.cmet.2012.03.005. View

Orozco L, Morselli M, Rubbi L, Guo W, Go J, Shi H . Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice. Cell Metab. 2015; 21(6):905-17. PMC: 4454894. DOI: 10.1016/j.cmet.2015.04.025. View

Xu X, Su S, Barnes V, De Miguel C, Pollock J, Ownby D . A genome-wide methylation study on obesity: differential variability and differential methylation. Epigenetics. 2013; 8(5):522-33. PMC: 3741222. DOI: 10.4161/epi.24506. View

Barres R, Kirchner H, Rasmussen M, Yan J, Kantor F, Krook A . Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep. 2013; 3(4):1020-7. DOI: 10.1016/j.celrep.2013.03.018. View

Birkenfeld A, Shulman G . Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2013; 59(2):713-23. PMC: 3946772. DOI: 10.1002/hep.26672. View

Maksimovic J, Gordon L, Oshlack A . SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. Genome Biol. 2012; 13(6):R44. PMC: 3446316. DOI: 10.1186/gb-2012-13-6-r44. View

Brown M, Goldstein J . Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008; 7(2):95-6. DOI: 10.1016/j.cmet.2007.12.009. View

Blattler A, Farnham P . Cross-talk between site-specific transcription factors and DNA methylation states. J Biol Chem. 2013; 288(48):34287-94. PMC: 3843044. DOI: 10.1074/jbc.R113.512517. View

Dedeurwaerder S, Defrance M, Calonne E, Denis H, Sotiriou C, Fuks F . Evaluation of the Infinium Methylation 450K technology. Epigenomics. 2011; 3(6):771-84. DOI: 10.2217/epi.11.105. View

10.

HARTMAN M, Kociba G, Hai T . The roles of ATF3 in glucose homeostasis. A transgenic mouse model with liver dysfunction and defects in endocrine pancreas. J Biol Chem. 2001; 276(31):29507-14. DOI: 10.1074/jbc.M100986200. View

11.

Nawa T, Nawa M, Cai Y, Zhang C, Uchimura I, Narumi S . Repression of TNF-alpha-induced E-selectin expression by PPAR activators: involvement of transcriptional repressor LRF-1/ATF3. Biochem Biophys Res Commun. 2000; 275(2):406-11. DOI: 10.1006/bbrc.2000.3332. View

12.

Howarth D, Lindtner C, Vacaru A, Sachidanandam R, Tsedensodnom O, Vasilkova T . Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet. 2014; 10(5):e1004335. PMC: 4038464. DOI: 10.1371/journal.pgen.1004335. View

13.

Multhaup M, Seldin M, Jaffe A, Lei X, Kirchner H, Mondal P . Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes. Cell Metab. 2015; 21(1):138-49. PMC: 4340475. DOI: 10.1016/j.cmet.2014.12.014. View

14.

Bibikova M, Le J, Barnes B, Saedinia-Melnyk S, Zhou L, Shen R . Genome-wide DNA methylation profiling using Infinium® assay. Epigenomics. 2011; 1(1):177-200. DOI: 10.2217/epi.09.14. View

15.

Samuel V, Liu Z, Qu X, Elder B, Bilz S, Befroy D . Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004; 279(31):32345-53. DOI: 10.1074/jbc.M313478200. View

16.

Barres R, Yan J, Egan B, Treebak J, Rasmussen M, Fritz T . Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012; 15(3):405-11. DOI: 10.1016/j.cmet.2012.01.001. View

17.

Kirchner H, Nylen C, Laber S, Barres R, Yan J, Krook A . Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass. Surg Obes Relat Dis. 2014; 10(4):671-8. DOI: 10.1016/j.soard.2013.12.019. View

18.

Barres R, Osler M, Yan J, Rune A, Fritz T, Caidahl K . Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab. 2009; 10(3):189-98. DOI: 10.1016/j.cmet.2009.07.011. View

19.

Fisher S, Kahn C . Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. J Clin Invest. 2003; 111(4):463-8. PMC: 151923. DOI: 10.1172/JCI16426. View

20.

Egan B, Zierath J . Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013; 17(2):162-84. DOI: 10.1016/j.cmet.2012.12.012. View