BRD4 regulates fructose-inducible lipid accumulation-related genes in the mouse liver.
Fructose intake induces hepatic steatosis by activating fat synthesis. In this study, we searched for genes that showed acute induction in the livers of mice force-fed with fructose, and examined how this induction is regulated.



We identified genes induced at 6h after the fructose force-feeding using a microarray and quantitative real-time RT-PCR. Histone acetylation and an acetylated histone binding protein bromodomain containing (BRD)4 binding around the fructose-inducible genes were examined using a chromatin immunoprecipitation assay. We examined whether (+)-JQ1, an inhibitor of the binding between the BRD4 and acetylated histones, inhibited the expressions of fructose-inducible genes, histone acetylation and BRD4 binding around the genes.



We identified upregulated genes related to lipid accumulation, such as Cyp8b1, Dak and Plin5, in mice force-fed with fructose compared with those force-fed with glucose. Acetylation of histones H3 and H4, and BRD4 binding around the transcribed region of those fructose-inducible genes, were enhanced by fructose force-feeding. Meanwhile, (+)-JQ1 treatment reduced expressions of fructose-inducible genes, histone acetylation and BRD4 binding around these genes.



Acute induction of genes related to lipid accumulation in the livers of mice force-fed with fructose is associated with the induction of histone acetylation and BRD4 binding around these genes.
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Laboratory of Nutritional Physiology, University of Shizuoka, Shizuoka, Japan.
Aki
A
Yamada
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Laboratory of Nutritional Physiology, University of Shizuoka, Shizuoka, Japan.
Kazue
K
Honma
Laboratory of Food and Nutritional Sciences, Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan.
Kazuki
K
Mochizuki
Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, Laboratory of Nutritional Physiology, University of Shizuoka, Shizuoka, Japan. Electronic address: gouda@u-shizuoka-ken.ac.jp.
Toshinao
T
Goda
D000107:Acetylation; D000818:Animals; D005632:Fructose / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070797:Perilipin-5 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013253:Steroid 12-alpha-Hydroxylase / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
D005632:Fructose; D006657:Histones; D009687:Nuclear Proteins; D000070797:Perilipin-5; D013253:Steroid 12-alpha-Hydroxylase; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins
BRD4; Fructose; Histone acetylation; Lipid metabolism; Liver