Hypermethylation of Hepatic Glucokinase and L-Type Pyruvate Kinase Promoters in High-Fat Diet–Induced Obese Rats

• Published in: Endocrinology (Philadelphia) 2011-04, Vol.152 (4), p.1284-1289
• Main Authors: Jiang, Minghong, Zhang, Yuhao, Liu, Meng, Lan, Michael Shihli, Fei, Jing, Fan, Weiwei, Gao, Xin, Lu, Daru
• Format: Article
• Language: English
• Subjects: 5-aza-2'-deoxycytidine; Age; Aging; Aging (natural); Animals; Biological and medical sciences; Cell culture; Cell Line; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diet; Dietary Fats - adverse effects; Diets; DNA; DNA methylation; DNA Methylation - genetics; Down-regulation; Enzymes; Fatty liver; Fundamental and applied biological sciences. Psychology; Gene expression; Glucokinase; Glucokinase - genetics; Glucose metabolism; Glycolysis; High fat diet; Insulin; Insulin resistance; Insulin Resistance - physiology; Kinases; Liver - enzymology; Liver - metabolism; Male; Medical sciences; Metabolic diseases; Metabolic disorders; Obesity; Obesity - chemically induced; Obesity - genetics; Palmitates - adverse effects; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; Promoters; Pyruvate kinase; Pyruvate Kinase - genetics; Pyruvic acid; Rats; Rats, Wistar; Steatosis; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-1162

DNA hypermethylation is correlated with a decline in hepatic glucokinase and L-type pyruvate kinase expression 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.