FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.
FoxO transcription factors are important targets of insulin action. To better understand the role of FoxO proteins in the liver, we created transgenic mice expressing constitutively active FoxO1 in the liver using the alpha1-antitrypsin promoter. Fasting glucose levels are increased, and glucose tolerance is impaired in transgenic (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride and cholesterol levels are reduced despite hyperinsulinemia, and post-prandial changes in triglyceride levels are markedly suppressed in TGN versus WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C and protein kinase B) and the ability to suppress beta-hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with (3)H(2)O is suppressed by approximately 70% in the liver of TGN versus WT mice after refeeding. Gene-array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport, and amino acid catabolism is increased, whereas genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, lipogenesis, and sterol synthesis pathways are suppressed in TGN versus WT. Studies with adenoviral vectors in isolated hepatocytes confirm that FoxO1 stimulates expression of gluconeogenic genes and suppresses expression of genes involved in glycolysis, the shunt pathway, and lipogenesis, including glucokinase and SREBP-1c. Together, these results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver, including glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways.
Zhang
Wenwei
W
Departments of Medicine and Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Patil
Sandip
S
Chauhan
Balwant
B
Guo
Shaodong
S
Powell
David R
DR
Le
Jamie
J
Klotsas
Angelos
A
Matika
Ryan
R
Xiao
Xiangshan
X
Franks
Roberta
R
Heidenreich
Kim A
KA
Sajan
Mini P
MP
Farese
Robert V
RV
Stolz
Donna Beer
DB
Tso
Patrick
P
Koo
Seung-Hoi
SH
Montminy
Marc
M
Unterman
Terry G
TG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001671:Biochemistry / Q000379:methods; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018076:DNA, Complementary / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D016678:Genome; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D050155:Lipogenesis; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics
D001786:Blood Glucose; D018076:DNA, Complementary; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D000515:alpha 1-Antitrypsin; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D008071:Lipoprotein Lipase; D005947:Glucose; D005990:Glycerol