Other
19 Authors
- Frank PG,
- Chow CW,
- Lisanti MP,
- Yang TT,
- Brancho D,
- Kim JY,
- Olabisi O,
- Yu RY,
- Lefer DJ,
- Suk HY,
- Calvert JW,
- Scherer PE,
- Hirsch E,
- Molkentin JD,
- Zhou C,
- Ghigo A,
- Jin J,
- Zhu H,
- Yang X
| First Author | Suk HY | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 5 | Pages | 3477-88 |
| PubMed ID | 23258544 | Mgi Jnum | J:195655 |
| Mgi Id | MGI:5484978 | Doi | 10.1074/jbc.M112.419150 |
| Citation | Suk HY, et al. (2013) Ablation of calcineurin Abeta reveals hyperlipidemia and signaling cross-talks with phosphodiesterases. J Biol Chem 288(5):3477-88 |
| abstractText | 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 beta-cell growth and adipokine gene transcription, its role in lipid homeostasis is poorly understood. Here, we examined lipid homeostasis in mice lacking calcineurin Abeta (CnAbeta(-/-)). We show that mice lacking calcineurin Abeta are hyperlipidemic and develop age-dependent insulin resistance. Hyperlipidemia found in CnAbeta(-/-) mice is, in part, due to increased lipolysis in adipose tissues, a process mediated by beta-adrenergic G-protein-coupled receptor signaling pathways. CnAbeta(-/-) 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 CnAbeta(-/-) mice or upon CsA treatment to inhibit calcineurin. Increased PKA activation and cAMP accumulation in CnAbeta(-/-) 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. |
