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

Xiyuan Zhang, Dan Zhou, Rita Strakovsky, Yukun Zhang, Yuan Xiang Pan

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)G558-G564
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number5
StatePublished - Mar 2012


  • Aging
  • Cancer
  • Chromatin
  • Nonalcoholic fatty liver disease
  • Stress

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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