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PMID: 19850873 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 44 ·2009-11-03 ·Pages 18831-6

Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, Stevens RD, Ilkayeva O, Newgard CB, Chan L, Moore DD

Abstract

Constitutive androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here we use leptin-deficient mice (ob/ob) and ob/ob, CAR(-/-) double mutant mice to identify a metabolic role of CAR in type 2 diabetes. Activation of CAR significantly reduces serum glucose levels and improves glucose tolerance and insulin sensitivity. Gene expression analyses and hyperinsulinemic euglycemic clamp results suggest that CAR activation ameliorates hyperglycemia by suppressing glucose production and stimulating glucose uptake and usage in the liver. In addition, CAR activation dramatically improves fatty liver by both inhibition of hepatic lipogenesis and induction of beta-oxidation. We conclude that CAR activation improves type 2 diabetes, and that these actions of CAR suggest therapeutic approaches to the disease.

MeSH Terms
Animals Blood Glucose/drug effects,metabolism Constitutive Androstane Receptor Diabetes Mellitus, Experimental/blood,complications,pathology,prevention & control Fatty Liver/blood,complications,pathology,prevention & control Gene Expression Regulation/drug effects Glucose Tolerance Test Insulin/pharmacology Lipogenesis/drug effects,genetics Liver/drug effects,enzymology,pathology Mice Mice, Obese Oxidation-Reduction/drug effects Receptors, Cytoplasmic and Nuclear/metabolism Sulfotransferases/metabolism
Chemicals
Blood Glucose Constitutive Androstane Receptor Insulin Nr1i3 protein, mouse Receptors, Cytoplasmic and Nuclear Sulfotransferases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Dong Bingning
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Saha Pradip K
Huang Wendong
Chen Wenling
Abu-Elheiga Lutfi A
Wakil Salih J
Stevens Robert D
Ilkayeva Olga
Newgard Christopher B
Chan Lawrence
Moore David D
References (39)
39 references, click to expand
  1. Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus.
    Diabetes Res. 1989 Feb;10(2):85-92 PMID: 2501061
  2. Hepatic drug metabolism and the activities of NADPH generating enzymes and glucose-6-phosphatase in phenobarbital treated genetically obese (ob/ob) mice.
    Biomed Pharmacother. 1987;41(7):389-96 PMID: 2833324
  3. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes.
    Mol Cell Biol. 2004 Sep;24(18):7931-40 PMID: 15340055
  4. Farnesoid X receptor is essential for normal glucose homeostasis.
    J Clin Invest. 2006 Apr;116(4):1102-9 PMID: 16557297
  5. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):5987-92 PMID: 9600904
  6. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets.
    Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10207-12 PMID: 12920182
  7. The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress.
    J Lipid Res. 2009 Mar;50(3):439-445 PMID: 18941143
  8. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6409-14 PMID: 15096593
  9. A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification.
    Mol Pharmacol. 2004 Feb;65(2):292-300 PMID: 14742670
  10. Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.
    PLoS Genet. 2008 Mar 14;4(3):e1000034 PMID: 18369453
  11. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.
    Nat Med. 2004 Mar;10(3):268-74 PMID: 14770177
  12. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.
    Diabetes. 2002 Jan;51(1):7-18 PMID: 11756317
  13. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.
    J Clin Invest. 2006 Mar;116(3):817-24 PMID: 16485039
  14. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha.
    J Biol Chem. 2006 May 26;281(21):14537-46 PMID: 16492670
  15. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression.
    Mol Pharmacol. 2008 Apr;73(4):1282-9 PMID: 18187584
  16. The cellular fate of glucose and its relevance in type 2 diabetes.
    Endocr Rev. 2004 Oct;25(5):807-30 PMID: 15466941
  17. CAR, the continuously advancing receptor, in drug metabolism and disease.
    Curr Drug Metab. 2005 Aug;6(4):329-39 PMID: 16101572
  18. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects.
    Diabetes. 1985 Sep;34(9):911-6 PMID: 3896900
  19. Determination of SCH 211803 by nanoelectrospray infusion mass spectrometry: evaluation of matrix effect and comparison with liquid chromatography-tandem mass spectrometry.
    J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Oct 5;809(2):205-10 PMID: 15315766
  20. DRUG-INDUCED CHANGES IN THE LIVER ENDOPLASMIC RETICULUM: ASSOCIATION WITH DRUG-METABOLIZING ENZYMES.
    Science. 1963 Dec 27;142(3600):1657-8 PMID: 14075694
  21. Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.
    J Biol Chem. 2006 Aug 4;281(31):22342-22351 PMID: 16740637
  22. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver.
    Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11245-50 PMID: 15266058
  23. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR.
    Science. 2002 Oct 11;298(5592):422-4 PMID: 12376703
  24. From mice to men: insights into the insulin resistance syndromes.
    Annu Rev Physiol. 2006;68:123-58 PMID: 16460269
  25. Inhibition of gluconeogenesis in isolated rat hepatocytes after chronic treatment with phenobarbital.
    Biochem J. 1991 Dec 15;280 ( Pt 3):663-9 PMID: 1764030
  26. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice.
    Cell Metab. 2007 Jan;5(1):73-9 PMID: 17189208
  27. PPARdelta regulates glucose metabolism and insulin sensitivity.
    Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3444-9 PMID: 16492734
  28. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.
    Cell Metab. 2008 Jan;7(1):45-56 PMID: 18177724
  29. Malonyl-CoA, a key signaling molecule in mammalian cells.
    Annu Rev Nutr. 2008;28:253-72 PMID: 18598135
  30. Effects of phenobarbital and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene on differentiated functions in mouse liver.
    Chem Biol Interact. 1987;64(1-2):83-92 PMID: 2446787
  31. Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse.
    World J Gastroenterol. 2007 Nov 14;13(42):5635-41 PMID: 17948939
  32. Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic.
    Diabetes. 2004 Jul;53(7):1633-42 PMID: 15220184
  33. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity.
    J Biol Chem. 2009 Sep 18;284(38):25984-92 PMID: 19617349
  34. Gene expression profiling of rat liver treated with serum triglyceride-decreasing compounds.
    J Toxicol Sci. 2007 Oct;32(4):387-99 PMID: 17965553
  35. Treatment of noninsulin-dependent diabetes mellitus with enzyme inducers.
    Clin Pharmacol Ther. 1983 Jun;33(6):826-35 PMID: 6851415
  36. Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis.
    Arch Toxicol. 2004 Aug;78(8):435-42 PMID: 15107969
  37. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function.
    J Exp Biol. 2003 Jun;206(Pt 12):2049-57 PMID: 12756287
  38. ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease.
    J Clin Invest. 2004 Feb;113(3):434-40 PMID: 14755340
  39. 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
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0909731106
Published
2009-11-03
Epub
2009-00-22
Pages
18831-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2773998
Subset
IM
Grants
NIDDK NIH HHS · R01 DK046546 · United States
NIDDK NIH HHS · P30-DK079638 · United States
NIDDK NIH HHS · R01-DK068037 · United States
NIDDK NIH HHS · R01 DK068037 · United States
NIDDK NIH HHS · R01 DK46546 · United States
NIDDK NIH HHS · P30 DK079638 · United States
External Links
PubMed source DOI: 10.1073/pnas.0909731106 PMC Full Text View journal details
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