Ablation of calcineurin Aβ reveals hyperlipidemia and signaling cross-talks with phosphodiesterases.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Signal Transduction*/drug effects; Calcineurin/*deficiency ; Cyclic Nucleotide Phosphodiesterases, Type 3/*metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/*metabolism ; Hyperlipidemias/*enzymology; Aging/drug effects ; Aging/pathology ; Amino Acid Sequence ; Animals ; COS Cells ; Calcineurin/metabolism ; Chlorocebus aethiops ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3/chemistry ; Cyclosporine/pharmacology ; Embryo, Mammalian/cytology ; Enzyme Activation/drug effects ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Hyperlipidemias/pathology ; Insulin Resistance ; Lipid Metabolism/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Phosphodiesterase Inhibitors/pharmacology ; Receptors, Adrenergic, beta/metabolism ; Triglycerides/biosynthesis
    • Abstract:
      Insulin resistance, hyperlipidemia, and cardiovascular complications are common dysregulations of metabolic syndrome. Transplant patients treated with immunosuppressant drugs such as cyclosporine A (CsA), an inhibitor of calcineurin phosphatase, frequently develop similar metabolic complications. Although calcineurin is known to mediate insulin sensitivity by regulating β-cell growth and adipokine gene transcription, its role in lipid homeostasis is poorly understood. Here, we examined lipid homeostasis in mice lacking calcineurin Aβ (CnAβ(-/-)). We show that mice lacking calcineurin Aβ are hyperlipidemic and develop age-dependent insulin resistance. Hyperlipidemia found in CnAβ(-/-) mice is, in part, due to increased lipolysis in adipose tissues, a process mediated by β-adrenergic G-protein-coupled receptor signaling pathways. CnAβ(-/-) mice also exhibit additional pathophysiological phenotypes caused by the potentiated GPCR signaling pathways. A cell autonomous mechanism with sustained cAMP/PKA activation is found in CnAβ(-/-) mice or upon CsA treatment to inhibit calcineurin. Increased PKA activation and cAMP accumulation in CnAβ(-/-) mice, however, are sensitive to phosphodiesterase inhibitor. Indeed, we show that calcineurin regulates degradation of phosphodiesterase 3B, in addition to phosphodiesterase 4D. These results establish a role for calcineurin in lipid homeostasis. These data also indicate that potentiated cAMP signaling pathway may provide an alternative molecular pathogenesis for the metabolic complications elicited by CsA in transplant patients.
    • References:
      Obes Res. 1995 Nov;3 Suppl 4:501S-505S. (PMID: 8697050)
      Diabetes. 2011 Nov;60(11):2892-902. (PMID: 21940781)
      Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):98-105. (PMID: 14563650)
      Nature. 1993 Sep 23;365(6444):352-5. (PMID: 8397339)
      Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1784-9. (PMID: 10677535)
      Mol Cell Biol. 2006 Aug;26(15):5784-96. (PMID: 16847331)
      Nature. 2006 Jun 1;441(7093):595-600. (PMID: 16554754)
      Metabolism. 1987 Mar;36(3):251-5. (PMID: 3821505)
      Genes Dev. 2003 Sep 15;17(18):2205-32. (PMID: 12975316)
      PLoS One. 2010 Aug 03;5(8):e11969. (PMID: 20689817)
      J Histochem Cytochem. 1996 Jan;44(1):13-8. (PMID: 8543776)
      Dev Cell. 2012 Jul 17;23(1):21-34. (PMID: 22814600)
      Physiol Rev. 2000 Oct;80(4):1483-521. (PMID: 11015619)
      J Pharmacol Exp Ther. 2000 Aug;294(2):778-83. (PMID: 10900260)
      Biochem Biophys Res Commun. 2007 Feb 23;353(4):1080-5. (PMID: 17198676)
      J Endocrinol Invest. 2000 Jul-Aug;23(7):482-90. (PMID: 11005276)
      Biochim Biophys Acta. 2007 Apr;1773(4):584-92. (PMID: 17320989)
      Biochem Biophys Res Commun. 1997 Jun 18;235(2):271-5. (PMID: 9199180)
      Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9398-403. (PMID: 12091710)
      Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4650-5. (PMID: 10200317)
      J Biol Chem. 2004 Apr 9;279(15):15214-22. (PMID: 14736883)
      Trends Endocrinol Metab. 2008 Mar;19(2):65-73. (PMID: 18291668)
      Am J Pathol. 2004 Nov;165(5):1755-65. (PMID: 15509543)
      Mol Cell Biol. 2008 May;28(10):3489-501. (PMID: 18347059)
      Cell. 2001 Jun 29;105(7):863-75. (PMID: 11439183)
      Nature. 2006 Sep 21;443(7109):345-9. (PMID: 16988714)
      J Clin Endocrinol Metab. 2002 Jul;87(7):3019-22. (PMID: 12107193)
      Biochem Soc Trans. 2007 Nov;35(Pt 5):1064-8. (PMID: 17956280)
      J Histochem Cytochem. 2001 Feb;49(2):187-95. (PMID: 11156687)
      J Exp Med. 1996 Feb 1;183(2):413-20. (PMID: 8627154)
      Curr Top Cell Regul. 2000;36:237-95. (PMID: 10842755)
      J Biol Chem. 2006 Jun 16;281(24):16591-8. (PMID: 16611631)
      Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4586-91. (PMID: 11904392)
      J Clin Invest. 2000 Jul;106(2):171-6. (PMID: 10903330)
      Curr Opin Immunol. 2003 Jun;15(3):299-307. (PMID: 12787755)
      Immunol Today. 1992 Apr;13(4):136-42. (PMID: 1374612)
      Genomics. 1996 Sep 15;36(3):476-85. (PMID: 8884271)
      Diabetes. 2004 Feb;53(2):276-84. (PMID: 14747276)
      JAMA. 1989 Jul 7;262(1):53-6. (PMID: 2733125)
      Essays Biochem. 2005;41:15-30. (PMID: 16250895)
      Endocr Rev. 2008 Oct;29(6):647-76. (PMID: 18606873)
      Diabetes Care. 2002 Mar;25(3):583-92. (PMID: 11874952)
      Mol Cell. 2011 Apr 8;42(1):84-95. (PMID: 21474070)
      Annu Rev Nutr. 2007;27:79-101. (PMID: 17313320)
      Annu Rev Pharmacol Toxicol. 2004;44:297-323. (PMID: 14744248)
      Nature. 1992 Jun 25;357(6380):695-7. (PMID: 1377362)
      Mol Cell Biol. 2010 Sep;30(18):4379-90. (PMID: 20647544)
      Genes Dev. 2003 Dec 15;17(24):3062-74. (PMID: 14681206)
      Biochim Biophys Acta. 2008 Jan;1784(1):16-26. (PMID: 17996741)
      FEBS Lett. 1980 Aug 25;118(1):18-24. (PMID: 6250905)
      Curr Opin Lipidol. 2003 Jun;14(3):281-7. (PMID: 12840659)
      Curr Opin Pharmacol. 2011 Dec;11(6):676-82. (PMID: 22001403)
      Mol Cell Biol. 2009 Jul;29(14):3845-52. (PMID: 19433446)
      Biochem J. 2003 Feb 15;370(Pt 1):1-18. (PMID: 12444918)
      Biochem Soc Trans. 2008 Oct;36(Pt 5):901-4. (PMID: 18793158)
      Mol Cell. 2007 Dec 14;28(5):730-8. (PMID: 18082598)
      Diabetologia. 2003 Sep;46(9):1179-89. (PMID: 12904862)
      Mol Pharmacol. 2001 Oct;60(4):873-9. (PMID: 11562451)
      Prog Nucleic Acid Res Mol Biol. 2001;66:241-77. (PMID: 11051766)
      Ann N Y Acad Sci. 2006 Nov;1083:129-52. (PMID: 17148737)
      Mol Cell Biol. 2006 Oct;26(20):7372-87. (PMID: 16908540)
      Annu Rev Physiol. 2003;65:333-47. (PMID: 12471167)
      J Biol Chem. 2001 Jan 26;276(4):2313-6. (PMID: 11096121)
      J Biol Chem. 2010 Dec 17;285(51):40050-9. (PMID: 20943662)
      Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2980-6. (PMID: 16877550)
    • Grant Information:
      R21 AI082501 United States AI NIAID NIH HHS; United States HHMI Howard Hughes Medical Institute; 5T32 GM07491 United States GM NIGMS NIH HHS; T32 GM007288 United States GM NIGMS NIH HHS; T32 GM007491 United States GM NIGMS NIH HHS; R01 DK090481 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Phosphodiesterase Inhibitors)
      0 (Receptors, Adrenergic, beta)
      0 (Triglycerides)
      83HN0GTJ6D (Cyclosporine)
      E0399OZS9N (Cyclic AMP)
      EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
      EC 3.1.3.16 (Calcineurin)
      EC 3.1.3.16 (protein phosphatase 3, catalytic subunit, beta isoform, mouse)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
    • Publication Date:
      Date Created: 20121222 Date Completed: 20130328 Latest Revision: 20240630
    • Publication Date:
      20240630
    • Accession Number:
      PMC3561567
    • Accession Number:
      10.1074/jbc.M112.419150
    • Accession Number:
      23258544