The coactivator SRC-1 is an essential coordinator of hepatic glucose production.
Gluconeogenesis makes a major contribution to hepatic glucose production, a process critical for survival in mammals. In this study, we identify the p160 family member, SRC-1, as a key coordinator of the hepatic gluconeogenic program in vivo. SRC-1-null mice displayed hypoglycemia secondary to a deficit in hepatic glucose production. Selective re-expression of SRC-1 in the liver restored blood glucose levels to a normal range. SRC-1 was found induced upon fasting to coordinate in a cell-autonomous manner, the gene expression of rate-limiting enzymes of the gluconeogenic pathway. At the molecular level, the main role of SRC-1 was to modulate the expression and the activity of C/EBPα through a feed-forward loop in which SRC-1 used C/EBPα to transactivate pyruvate carboxylase, a crucial gene for initiation of the gluconeogenic program. We propose that SRC-1 acts as a critical mediator of glucose homeostasis in the liver by adjusting the transcriptional activity of key genes involved in the hepatic glucose production machinery.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Jean-Francois
JF
Louet
Atul R
AR
Chopra
Jorn V
JV
Sagen
Jie
J
An
Brian
B
York
Mounia
M
Tannour-Louet
Pradip K
PK
Saha
Robert D
RD
Stevens
Brett R
BR
Wenner
Olga R
OR
Ilkayeva
James R
JR
Bain
Suoling
S
Zhou
Franco
F
DeMayo
Jianming
J
Xu
Christopher B
CB
Newgard
Bert W
BW
O'Malley
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis*; D007003:Hypoglycemia / Q000378:metabolism*; D047468:Immunoprecipitation; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D016133:Polymerase Chain Reaction
C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D005947:Glucose