肥胖和2型糖尿病患者肝脏中糖酵解及脂肪生成基因的DNA甲基化改变。
Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients.
作者信息
Kirchner Henriette, Sinha Indranil, Gao Hui, Ruby Maxwell A, Schönke Milena, Lindvall Jessica M, Barrès Romain, Krook Anna, Näslund Erik, Dahlman-Wright Karin, Zierath Juleen R
机构信息
Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Department Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
出版信息
Mol Metab. 2016 Jan 2;5(3):171-183. doi: 10.1016/j.molmet.2015.12.004. eCollection 2016 Mar.
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.
目的
表观遗传修饰参与2型糖尿病的病因学。
方法
我们对患有或未患有2型糖尿病的重度肥胖男性以及非肥胖男性的肝脏进行了全基因组甲基化组和转录组分析，以发现胰岛素抵抗发展背后的异常通路。结果通过焦磷酸测序进行验证。
结果
我们发现参与肝脏糖酵解和胰岛素抵抗的基因发生低甲基化，同时mRNA表达和蛋白质水平增加。焦磷酸测序显示，在重度肥胖非糖尿病和2型糖尿病患者肝脏中的其中四个基因中，ATF基序内的CpG位点发生低甲基化，提示通过改变ATF与DNA的结合对转录进行表观遗传调控。
结论
重度肥胖非糖尿病和2型糖尿病患者的肝脏甲基化组和转录组存在明显改变，在ATF基序调控位点内有几个控制葡萄糖代谢的基因发生低甲基化。肥胖似乎使肝脏的表观遗传程序向糖酵解和脂肪生成增加的方向转变，这可能会加剧胰岛素抵抗的发展。
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