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PMID: 19416713 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones.

Cell metabolism ·Vol. 9 ·No. 5 ·2009-05-00 ·Pages 428-39

Wang XL, Suzuki R, Lee K, Tran T, Gunton JE, Saha AK, Patti ME, Goldfine A, Ruderman NB, Gonzalez FJ, Kahn CR

Abstract

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.

MeSH Terms
3-Hydroxybutyric Acid/blood AMP-Activated Protein Kinases/metabolism Adult Animals Aryl Hydrocarbon Receptor Nuclear Translocator/deficiency,genetics,metabolism CCAAT-Enhancer-Binding Protein-alpha/metabolism Diabetes Mellitus, Type 2/metabolism Female Gene Expression Gluconeogenesis Humans Insulin/analysis,metabolism Lipogenesis/genetics Liver/enzymology,metabolism Male Mice Mice, Knockout Middle Aged Phosphorylation Receptors, Cytoplasmic and Nuclear/metabolism Sterol Regulatory Element Binding Protein 1/metabolism Tumor Cells, Cultured
Chemicals
ARNT protein, human Arnt protein, mouse CCAAT-Enhancer-Binding Protein-alpha Insulin Receptors, Cytoplasmic and Nuclear Sterol Regulatory Element Binding Protein 1 farnesoid X-activated receptor Aryl Hydrocarbon Receptor Nuclear Translocator AMP-Activated Protein Kinases 3-Hydroxybutyric Acid
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Wang Xiaohui L
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Suzuki Ryo
Lee Kevin
Tran Thien
Gunton Jenny E
Saha Asish K
Patti Mary-Elizabeth
Goldfine Allison
Ruderman Neil B
Gonzalez Frank J
Kahn C Ronald
References (33)
33 references, click to expand
  1. Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT).
    Mol Cell Biol. 1994 Sep;14(9):6075-86 PMID: 8065341
  2. Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene.
    J Biol Chem. 1989 Jun 5;264(16):9657-64 PMID: 2542317
  3. Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.
    EMBO J. 2007 Feb 21;26(4):1081-93 PMID: 17290224
  4. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1.
    Annu Rev Cell Dev Biol. 1999;15:551-78 PMID: 10611972
  5. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.
    Mol Cell. 2000 Jul;6(1):87-97 PMID: 10949030
  6. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c.
    Biochem J. 2002 Sep 1;366(Pt 2):377-91 PMID: 12061893
  7. AMP-activated protein kinase and type 2 diabetes.
    Curr Med Chem. 2006;13(5):583-9 PMID: 16515522
  8. Insulin signalling and the regulation of glucose and lipid metabolism.
    Nature. 2001 Dec 13;414(6865):799-806 PMID: 11742412
  9. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.
    Cell Metab. 2008 Feb;7(2):125-34 PMID: 18249172
  10. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4273-8 PMID: 9113979
  11. Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin.
    Mol Endocrinol. 2006 Nov;20(11):2831-47 PMID: 16840535
  12. AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats.
    Am J Physiol Endocrinol Metab. 2005 Nov;289(5):E794-800 PMID: 15956049
  13. knocking down liver ccaat/enhancer-binding protein alpha by adenovirus-transduced silent interfering ribonucleic acid improves hepatic gluconeogenesis and lipid homeostasis in db/db mice.
    Endocrinology. 2006 Jun;147(6):3060-9 PMID: 16543372
  14. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21.
    Cell Metab. 2007 Jun;5(6):415-25 PMID: 17550777
  15. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes.
    Cell. 2005 Aug 12;122(3):337-49 PMID: 16096055
  16. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.
    Nature. 2001 Sep 13;413(6852):131-8 PMID: 11557972
  17. The direct and indirect effects of insulin on hepatic glucose production in vivo.
    Diabetologia. 1998 Sep;41(9):987-96 PMID: 9754815
  18. Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle.
    Am J Physiol. 1997 Apr;272(4 Pt 1):E641-8 PMID: 9142886
  19. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.
    Cell. 2000 Sep 15;102(6):731-44 PMID: 11030617
  20. Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (Arnt) gene leads to loss of target gene induction by the aryl hydrocarbon receptor and hypoxia-inducible factor 1alpha.
    Mol Endocrinol. 2000 Oct;14(10):1674-81 PMID: 11043581
  21. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones.
    J Clin Invest. 2003 Aug;112(4):608-18 PMID: 12925701
  22. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.
    Nature. 2003 May 29;423(6939):550-5 PMID: 12754525
  23. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes.
    J Neurochem. 1999 Oct;73(4):1674-82 PMID: 10501215
  24. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat.
    Biochem J. 1983 Jul 15;214(1):21-8 PMID: 6615466
  25. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.
    J Clin Invest. 2002 May;109(9):1125-31 PMID: 11994399
  26. Identification of a cAMP response element within the glucose- 6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells.
    Biochem J. 1999 Mar 1;338 ( Pt 2):457-63 PMID: 10024523
  27. Hepatic malonyl-CoA levels of fed, fasted and diabetic rats as measured using a simple radioisotopic assay.
    J Biol Chem. 1978 Nov 25;253(22):8291-3 PMID: 711752
  28. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise.
    Acta Physiol Scand. 2003 Aug;178(4):435-42 PMID: 12864749
  29. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.
    Cell Metab. 2007 Jun;5(6):426-37 PMID: 17550778
  30. Fatty acid regulation of hepatic gene transcription.
    J Nutr. 2005 Nov;135(11):2503-6 PMID: 16251601
  31. Role of PAT proteins in lipid metabolism.
    Biochimie. 2005 Jan;87(1):45-9 PMID: 15733736
  32. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.
    Annu Rev Physiol. 1992;54:885-909 PMID: 1562196
  33. Role of the liver in the control of carbohydrate and lipid homeostasis.
    Diabetes Metab. 2004 Nov;30(5):398-408 PMID: 15671906
Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2009.04.001
Published
2009-05-00
Pages
428-39
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC2803070
Subset
IM
Grants
NIDDK NIH HHS · R01 DK067509 · United States
NIDDK NIH HHS · R01 DK060837 · United States
NIDDK NIH HHS · DK-067509 · United States
NIDDK NIH HHS · DK-060837 · United States
NHLBI NIH HHS · P01 HL068758 · United States
Intramural NIH HHS · Z01 BC005708-17 · United States
NHLBI NIH HHS · P01HL68758 · United States
Databases
GEO
GSE15653
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1016/j.cmet.2009.04.001 PMC Full Text View journal details
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