ChREBP binding and histone modifications modulate hepatic expression of the Fasn gene in a metabolic syndrome rat model.
OBJECTIVE
Although the expression of hepatic lipogenic genes is enhanced in insulin resistance, the underlying mechanism is unclear. To reveal the details, the aim of this study was to investigate whether the expression of hepatic lipogenic genes are mediated by epigenetic regulation and specific transcription factors in an insulin resistance model of rats.


METHODS
Using a rat model of insulin resistance (SHR/NDmc-cp), we investigated the relationship between hepatic expression of the lipogenic gene fatty-acid synthase (Fasn), binding of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to the Fasn gene, and histone modifications in the region of the Fasn gene by real-time reverse transcriptase polymerase chain reaction, immunoblotting, and chromatin immunoprecipitation assay.


RESULTS
Compared with control rats, Fasn mRNA expression and protein levels were higher in the livers of SHR/NDmc-cp rats, as were protein expression levels and Fasn binding of ChREBP and RNA polymerase II. Moreover, compared with the livers of control rats, levels of mono-methylated histone H3 lysine (K) 4 and acetylated histone H4 were higher in the promoter/enhancer region of the Fasn gene in the livers of SHR/NDmc-cp rats. Levels of trimethylated histone H3K4 and acetylated histone H3 were higher in the transcribed region.


CONCLUSIONS
The results of this study indicate that expression of the Fasn gene in the livers of insulin-resistant rats is associated with increased H3K4 methylation, increased histone H3 acetylation, and increased H4 acetylation, and also, binding levels of ChREBP to promoter/enhancer region of Fasn gene is involved in the Fasn gene expression caused by hyperglycemia.
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Global COE Program, University of Shizuoka, Shizuoka, Japan; Food Environmental Design Course, Faculty of Education, Art and Science, Yamagata University, Yamagata, Japan.
Takuji
T
Suzuki
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Global COE Program, University of Shizuoka, Shizuoka, Japan.
Takeshi
T
Muramatsu
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Global COE Program, University of Shizuoka, Shizuoka, Japan.
Kousuke
K
Morioka
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Global COE Program, University of Shizuoka, Shizuoka, Japan.
Toshinao
T
Goda
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Global COE Program, University of Shizuoka, Shizuoka, Japan; Laboratory of Food and Nutritional Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan. Electronic address: Mochizukik@yamanashi.ac.jp.
Kazuki
K
Mochizuki
D000107:Acetylation; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D044127:Epigenesis, Genetic; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D042421:Histone Code; D006657:Histones / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006657:Histones; D007328:Insulin; C442825:Mlxipl protein, rat; D012333:RNA, Messenger; D064429:Fatty Acid Synthases; D008239:Lysine
ChREBP; Histone modifications; Insulin resistance; Lipogenesis; Liver