Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH.
Endoplasmic reticulum (ER)-bound transcription factor families are shown to be involved in the control of various metabolic pathways. Here, we report a critical function of ER-bound transcription factor, CREBH, in the regulation of hepatic gluconeogenesis. Expression of CREBH is markedly induced by fasting or in the insulin-resistant state in rodents in a dexamethasone- and PGC-1alpha-dependent manner, which results in the accumulation of active nuclear form of CREBH (CREBH-N). Overexpression of constitutively active CREBH activates transcription of PEPCK-C or G6Pase by binding to its enhancer site that is distinct from the well-characterized CREB/CRTC2 regulatory sequences in vivo. Of interest, knockdown of CREBH in liver significantly reduces blood glucose levels without altering expression of genes involved in the ER stress signaling cascades in mice. These data suggest a crucial role for CREBH in the regulation of hepatic glucose metabolism in mammals.
Lee
Min-Woo
MW
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.
Chanda
Dipanjan
D
Yang
Jianqi
J
Oh
Hyunhee
H
Kim
Su Sung
SS
Yoon
Young-Sil
YS
Hong
Sungpyo
S
Park
Keun-Gyu
KG
Lee
In-Kyu
IK
Choi
Cheol Soo
CS
Hanson
Richard W
RW
Choi
Hueng-Sik
HS
Koo
Seung-Hoi
SH
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000494:pharmacology; D014157:Transcription Factors
D001786:Blood Glucose; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D003907:Dexamethasone