title: Ablation of calcineurin Aβ reveals hyperlipidemia and signaling cross-talks with phosphodiesterases.
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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Hee Yun
authors.initials: HY
authors.lastname: Suk
authors.forename: Chen
authors.initials: C
authors.lastname: Zhou
authors.forename: Teddy T C
authors.initials: TT
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Raymond Y L
authors.initials: RY
authors.lastname: Yu
authors.forename: Opeyemi
authors.initials: O
authors.lastname: Olabisi
authors.forename: XiaoYong
authors.initials: X
authors.lastname: Yang
authors.forename: Deborah
authors.initials: D
authors.lastname: Brancho
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000172:deficiency* / Q000378:metabolism; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006949:Hyperlipidemias / Q000201:enzymology* / Q000473:pathology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D014280:Triglycerides; D016572:Cyclosporine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4