title: Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model.
abstract: Overnutrition, such as a high-fat (HF) diet, is a feature followed by some in developed nations that leads to obesity and fatty liver disease. In rats, when fed a fat-high diet, some develop obesity (obesity prone, OP) while others display an obesity-resistant (OR) phenotype. The present study investigated the differences between OP and OR rats on their activation of hepatic cellular senescence pathways on a HF diet. Male OP and OR rats were fed a HF diet containing 45% kcal from fat for 13 wk, and livers were collected for analysis by quantitative real-time PCR, Western blot, and chromatin immunoprecipitation. OP rats were 41% heavier than OR rats, despite consuming the same amount of food. Triacylglycerol levels were increased significantly in both plasma and liver of OP rats. Gene analysis demonstrated a significant increase of both the amount and the transcription rates of p16(INK4a) and p21(Cip1) mRNA in OP rats. The increased p16(INK4a) and p21(Cip1) also caused a significant decrease in the level of phosphorylation of retinoblastoma protein. In OP rats, the increase of p16(INK4a) was associated with the higher acetylation levels of histone H4 at the p16(INK4a) promoter and coding region and lower methylation level of histone H3 lysine-27 in the p16(INK4a) coding region. The increase of p21(Cip1) was associated with increased acetylation of both histone H3 and H4 and decreased trimethylation of histone H3 lysine-27 at the p21(Cip1) promoter. In the p21(Cip1) coding region, dimethylation of histone H3 lysine-4 was significantly higher (P <0.05) in livers of OP rats compared with OR rats.
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 61801, USA.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Rita
authors.initials: R
authors.lastname: Strakovsky
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Pan
mesh_terms: D000107:Acetylation; D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C493958:Cdkn1a protein, rat; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004041:Dietary Fats; D006657:Histones; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014280:Triglycerides