The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver.
Hepatic gluconeogenesis is crucial for glucose homeostasis. Although sirtuin 1 (Sirt1) is implicated in the regulation of gluconeogenesis in the liver, the effects of other histone deacetylases (HDAC) on gluconeogenesis are unclear. The aim of this study was to identify the role of class I HDACs in hepatic gluconeogenesis. In HepG2 cells and the liver of mice, the expressions of phosphoenol pyruvate carboxykinase (PEPCK) and hepatocyte nuclear factor 4α (HNF4α) were significantly decreased by treatment with a newly designed class I HDAC inhibitor, Ky-2. SiRNA knockdown of HDAC1 expression, but not of HDAC2 or HDAC3, in HepG2 cells decreased PEPCK and HNF4α expression. In HepG2 cells, insulin-stimulated phosphorylation of Akt and forkhead box O 1 (FoxO1) was increased by Ky-2. Pyruvate tolerance tests in Ky-2-treated high-fat-diet (HFD)-fed mice showed a marked reduction in blood glucose compared with vehicle-treated HFD mice. These data suggest that class I HDACs increase HNF4α protein expression and the transcriptional activity of FoxO1, followed by the induction of PEPCK mRNA expression and gluconeogenesis in liver.
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Hiroshi
H
Oiso
Noboru
N
Furukawa
Mihoshi
M
Suefuji
Seiya
S
Shimoda
Akihiro
A
Ito
Ryohei
R
Furumai
Junichi
J
Nakagawa
Minoru
M
Yoshida
Norikazu
N
Nishino
Eiichi
E
Araki
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors / Q000235:genetics; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic
D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; D056572:Histone Deacetylase Inhibitors; D007328:Insulin; C555819:Ky-2 cyclic peptide; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D056284:Histone Deacetylase 1; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose