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

Hee Yun Suk, Chen Zhou, Teddy T C Yang, Hong Zhu, Raymond Y L Yu, Opeyemi Olabisi, Xiao Yong Yang, Deborah Brancho, Ja Young Kim, Philipp E. Scherer, Philippe G. Frank, Michael P. Lisanti, John W. Calvert, David J. Lefer, Jeffery D. Molkentin, Alessandra Ghigo, Emilio Hirsch, Jianping Jin, Chi Wing Chow

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3477-3488
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number5
DOIs
StatePublished - Feb 1 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Suk, H. Y., Zhou, C., Yang, T. T. C., Zhu, H., Yu, R. Y. L., Olabisi, O., Yang, X. Y., Brancho, D., Kim, J. Y., Scherer, P. E., Frank, P. G., Lisanti, M. P., Calvert, J. W., Lefer, D. J., Molkentin, J. D., Ghigo, A., Hirsch, E., Jin, J., & Chow, C. W. (2013). Ablation of calcineurin Aβ reveals hyperlipidemia and signaling cross-talks with phosphodiesterases. Journal of Biological Chemistry, 288(5), 3477-3488. https://doi.org/10.1074/jbc.M112.419150