Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones.
We have previously shown that expression of the transcription factor ARNT/HIF1beta is reduced in islets of humans with type 2 diabetes. We have now found that ARNT is also reduced in livers of diabetics. To study the functional effect of its reduction, we created mice with liver-specific ablation (L-ARNT KO) using ARNT loxP mice and adenoviral-mediated delivery of Cre. L-ARNT KO mice had normal blood glucose but increased fed insulin levels. These mice also exhibited features of type 2 diabetes with increased hepatic gluconeogenesis, increased lipogenic gene expression, and low serum beta-hydroxybutyrate. These effects appear to be secondary to increased expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha), farnesoid X receptor (FXR), and sterol response element-binding protein 1c (SREBP-1c) and a reduction in phosphorylation of AMPK without changes in the expression of enzymes in ketogenesis, fatty acid oxidation, or FGF21. These results demonstrate that a deficiency of ARNT action in the liver, coupled with that in beta cells, could contribute to the metabolic phenotype of human type 2 diabetes.
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Xiaohui L
XL
Wang
Ryo
R
Suzuki
Kevin
K
Lee
Thien
T
Tran
Jenny E
JE
Gunton
Asish K
AK
Saha
Mary-Elizabeth
ME
Patti
Allison
A
Goldfine
Neil B
NB
Ruderman
Frank J
FJ
Gonzalez
C Ronald
CR
Kahn
D020155:3-Hydroxybutyric Acid / Q000097:blood*; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005943:Gluconeogenesis; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099150:Receptor, Farnesoid X-Activated
D020155:3-Hydroxybutyric Acid; D055372:AMP-Activated Protein Kinases; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D022763:CCAAT-Enhancer-Binding Protein-alpha; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D000099150:Receptor, Farnesoid X-Activated; C497396:ARNT protein, human; C497397:Arnt protein, mouse