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.

Epigenetics and Metabolism

“…153 Precisely, how these modifications are regulated remains to be determined 152 ; however, there is evidence to suggest that HFD could initiate epigenetic changes by regulating genes that encode histone modifying enzymes. High fat-fed transgenic adult mice expressing the human cholesterol transporter APOE2 (hAPOE2) gene exhibited significantly elevated hepatic lipid accumulation.…”

Chromatin Modifications Associated With Diabetes and Obesity

“…20 More recently, it has been shown that C57BL/6J mice fed a high fat diet to induce obesity display chromatin remodeling in liver tissue across the genome. 21 Furthermore, the greatest degree of remodeling was at regulatory regions bound by transcription factors (TFs) such as HNF4α, CEBP/α and FOXA1, and marked by histone lysine-4 monomethylation (H3K4me1), a chromatin modification associated with regulatory regions (Figure 2).…”

Nutrition, Genes and Modern Disease: A Current Dilemma or a Legacy of our Past

“…Zhang et al (2012) [42] showed that, in rats when fed a high fat diet, some developed obesity while others displayed an obesity-resistant phenotype. These authors demonstrated induction of senescence and aging pathways in obese rats via p16INK4a and p21Cip1 is associated with histone modifications (acetylation and methylation).…”