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- Title
Acute Ablation of ARNT/HIF1β in Liver Results in Elevated Gluconeogenesis, Hypoketonemia, and Dyslipidemia.
- Authors
Wang, Xiaohui L.; Suzuki, Ryo; Patti, Mary-Elizabeth; Goldfine, Allison; Gonzalez, Frank J.; Kahn, C. R.
- Abstract
Previous studies from our laboratory demonstrated that there is reduced expression of the transcription factor ARNT (HIF1β) in β-cells in humans with type 2 diabetes, and that this results in impaired insulin secretion and altered β-cell gone expression. Microarray analysis also revealed a 30% decrease in ARNT expression in liver of obese individuals with Type 2 diabetes (p<0.02). To study the functional effect of the reduction in ARNT, we injected ARNT loxP mice with adenoviral Cre to specifically ablate ARNT in liver. The L-ARNT[sup -/-] mice had normal blood glucose but increased fed insulin levels, suggesting insulin resistance. Hepatic glucose output was elevated under fasting conditions in L-ARNT[sup -/-] mice. In parallel, expression of key gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and fructose-1, 6-bisphosphatase (FBP), was increased several fold. L-ARNT[sup -/-] mice also exhibited very low serum beta-hydroxybutyrate levels. However, there were no significant changes in the expression of key enzymes in ketogenesis. Interestingly, despite no remarkable changes in the expression of genes involved in hepatic fatty acid beta-oxidation, such as AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase I (CPT-I), there was a reduction in phosphorylation of AMPK in the liver of L-ARNT[sup -/-] mice. There was also an increase in the expression of genes encoding liver X receptor (LXR), sterol response element-binding protein 1c (SREBP1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1), and a visible redistribution of hepatic lipid in the L-ARNT[sup -/-] mice. Taken together, these results demonstrate that ARNT plays an important role in regulating hepatic glucose homeostasis and lipid metabolism, and suggest that a deficiency of ARNT action in the liver in humans with type 2 diabetes could contribute to altered metabolic function of the liver. ADA-Funded Research
- Publication
Diabetes, 2007, Vol 56, pA393
- ISSN
0012-1797
- Publication type
Academic Journal