Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands
| Autor: | William M. Bailey, Michael H. Gelb, Boris B. Boyanovsky, Preetha Shridas, Rob C. Oslund, Nancy R. Webb |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Receptor expression Adrenocorticotropic hormone Phospholipase Biology Transfection Biochemistry Cell Line Mice chemistry.chemical_compound Adrenocorticotropic Hormone Corticosterone Internal medicine Adrenal Glands medicine Animals Group X Phospholipases A2 Luciferases Promoter Regions Genetic Liver X receptor Receptor Molecular Biology Cells Cultured Progesterone Mice Knockout Regulation of gene expression Reverse Transcriptase Polymerase Chain Reaction Steroidogenic acute regulatory protein Cell Biology Phosphoproteins Immunohistochemistry Molecular biology Mice Inbred C57BL Metabolism Endocrinology Gene Expression Regulation chemistry Mutation Female |
| Zdroj: | Journal of Biological Chemistry. 285:20031-20039 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109.090423 |
| Popis: | We developed C57BL/6 mice with targeted deletion of group X secretory phospholipase A(2) (GX KO). These mice have approximately 80% higher plasma corticosterone concentrations compared with wild-type (WT) mice under both basal and adrenocorticotropic hormone (ACTH)-induced stress conditions. This increased corticosterone level was not associated with increased circulating ACTH or a defect in the hypothalamic-pituitary axis as evidenced by a normal response to dexamethasone challenge. Primary cultures of adrenal cells from GX KO mice exhibited significantly increased corticosteroid secretion compared with WT cells. Conversely, overexpression of GX secretory phospholipase A(2) (sPLA(2)), but not a catalytically inactive mutant form of GX sPLA(2), significantly reduced steroid production 30-40% in Y1 mouse adrenal cell line. This effect was reversed by the sPLA(2) inhibitor, indoxam. Silencing of endogenous M-type receptor expression did not restore steroid production in GX sPLA(2)-overexpressing Y1 cells, ruling out a role for this sPLA(2) receptor in this regulatory process. Expression of steroidogenic acute regulatory protein (StAR), the rate-limiting protein in corticosteroid production, was approximately 2-fold higher in adrenal glands of GX KO mice compared with WT mice, whereas StAR expression was suppressed in Y1 cells overexpressing GX sPLA(2). Results from StAR-promoter luciferase reporter gene assays indicated that GX sPLA(2) antagonizes StAR promoter activity and liver X receptor-mediated StAR promoter activation. In summary, GX sPLA(2) is expressed in mouse adrenal glands and functions to negatively regulate corticosteroid synthesis, most likely by negatively regulating StAR expression. |
| Databáze: | OpenAIRE |
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