Ablation of ARNT/HIF1b in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones (Cell Metabolism, 2009, 9:428-439)

報告日期: 2010/05/18
報告時間: 15:10/16:00
報告學生: 許晉源
講評老師: 蔡曜聲
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/990420-1.pdf

Ablation of ARNT/HIF1β in Liver Alters Gluconeogenesis, Lipogenic Gene Expression, and Serum Ketones

Wang X. L., Suzuki R., Lee K., Tran T., Gunton J. E., Saha A. K., Patti M. E., Goldfine A., Ruderman N. B., Gonzalez F. J., Kahn C. R.

Cell Metabolism 9, 428–439 (2009)

 

Speaker:許晉源

Commentator:蔡曜聲 老師

Time: 2010/05/18 1510 - 1600

PlaceRoom 602

 

Abstract:

The liver plays a central role in the regulation of lipid and glucose homeostasis both in humans and rodents. The aryl hydrocarbon receptor nuclear translocator (ARNT), also known as hypoxia-inducible factor-1β (HIF-1β), can response to various environments and regulate, xenobiotic metabolism, angiogenesis, and normal embryonic development. Previous studies have shown that ARNT was decreased in β cells of humans with type 2 diabetes. In this study, the authors found that ARNT was also decreased in livers with type 2 diabetes. To investigate the role of ARNT reduction, the authors created liver-specific ablation (L-ARNT KO) mice by using ARNT loxP mice with adenovirus carrying Cre recombinase (Ad-Cre) into mice. L-ARNT KO mice had increased fed insulin levels but normal blood glucose. L-ARNT KO mice also showed features similar to type 2 diabetes, including increased hepatic gluconeogenesis, increased lipogenic gene expression, and lower serum β-hydroxybutyrate. These effects were mediated through activation of critical transcription factors in gluconeogenesis and lipogenesis, such as CCAAT/enhancer-binding protein alpha (C/EBPα), farnesoid X receptor (FXR), and sterol response element-binding protein 1c (SREBP-1c). The phosphorylation of AMPK was reduced without changes in the expression of enzymes in fatty acid oxidation, ketogenesis, or fibroblast growth factor 21 (FGF21). These results suggest that ARNT plays crucial roles in the regulation of metabolism in β cells and liver, and deficiency of ARNT could lead to the metabolic phenotype of human type 2 diabetes.

 

References:

1.       Saltiel A. R., Kahn C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799-806 (2001).

2.       Gunton J. E., Kulkarni R. N., Kahn C. R., et al. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122, 337-349 (2005).