Hypermethylation of hepatic glucokinase and L-type pyruvate kinase promoters in high-fat diet-induced obese rats.
Obesity-dependent insulin resistance and type 2 diabetes mellitus are closely associated with decreased glucose utilization and down-regulation of hepatic glycolytic enzymes expression. Previously, we showed that DNA hypermethylation is involved in age-dependent susceptibility to hepatic insulin resistance and diabetes. However, what we cannot distinguish is whether the age-related obesity contributes to DNA hypermethylation in those natural aging rats. In the present study, we hypothesize that DNA methylation plays a crucial role in the regulation of glycolytic enzymes in the high-fat diet-induced obesity. Here, we report that DNA hypermethylation is correlated with a decline in hepatic glucokinase (Gck) and L-type pyruvate kinase (LPK) expression in high-fat diet-induced obese rats as compared with the control diet group. Down-regulation of Gck and LPK expression are reversed by the 5-aza-2'-deoxycytidine in the cell model of steatosis. These novel observations indicate that DNA methylation is involved in the development of metabolic diseases, such as obesity, insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis, suggesting that the hypermethylation level of Gck and LPK promoters may be a useful parameter for the evaluation of obesity-induced insulin resistance and fatty liver.
State Key Laboratory of Genetic Engineering, Institute of Genetics and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China 200433.
Minghong
M
Jiang
Yuhao
Y
Zhang
Meng
M
Liu
Michael Shihli
MS
Lan
Jing
J
Fei
Weiwei
W
Fan
Xin
X
Gao
Daru
D
Lu
D000818:Animals; D002460:Cell Line; D019175:DNA Methylation / Q000235:genetics*; D004041:Dietary Fats / Q000009:adverse effects*; D005941:Glucokinase / Q000235:genetics*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000139:chemically induced / Q000235:genetics*; D010168:Palmitates / Q000009:adverse effects; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011770:Pyruvate Kinase / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar
D004041:Dietary Fats; D010168:Palmitates; D005941:Glucokinase; D011770:Pyruvate Kinase