Forkhead Box P1 (FOXP1) Transcription Factor Regulates Hepatic Glucose Homeostasis.
Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet-induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis.
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Yongkang
Y
Zou
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Ning
N
Gong
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Ying
Y
Cui
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Xiaojuan
X
Wang
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Anfang
A
Cui
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Qi
Q
Chen
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Tao
T
Jiao
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Xueyu
X
Dong
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Hao
H
Yang
the Beijing Friendship Hospital Affiliated to the Capital Medical University, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Digestive Disease Center, Beijing, China.
Shutian
S
Zhang
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and.
Fude
F
Fang
From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China and changy@ibms.pumc.edu.cn.
Yongsheng
Y
Chang
D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004041:Dietary Fats; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose
gluconeogenesis; glucose; hemostasis; transcription regulation; type 2 diabetes