Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model

Overnutrition, such as a highfat (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.