Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands

• Published in: The Journal of biological chemistry Vol. 285; no. 26; pp. 20031 - 20039
• Main Authors: Shridas, Preetha, Bailey, William M., Boyanovsky, Boris B., Oslund, Rob C., Gelb, Michael H., Webb, Nancy R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.06.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Adrenal Glands - cytology; Adrenal Glands - drug effects; Adrenal Glands - metabolism; Adrenocorticotropic Hormone - blood; Adrenocorticotropic Hormone - pharmacology; Animals; Arachidonic Acid; Cell Line; Cells, Cultured; Corticosterone - blood; Corticosterone - metabolism; Female; Gene Expression Regulation; Group X Phospholipases A2 - genetics; Group X Phospholipases A2 - metabolism; Immunohistochemistry; Indoxam; Liver X Receptors; Luciferases - genetics; Luciferases - metabolism; M-type Receptor; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Phospholipase; Phosphoproteins - genetics; Phosphoproteins - metabolism; Progesterone - metabolism; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; Steroid; Steroidogenic Acute Regulatory Protein; Transcription Regulation; Transfection; Y-1 Adrenal Cell Line; Steroid; Phospholipase; Transcription Regulation; M-type Receptor; Indoxam; Steroidogenic Acute Regulatory Protein; Y-1 Adrenal Cell Line; Liver X Receptors; Metabolism; Arachidonic Acid
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M109.090423

We developed C57BL/6 mice with targeted deletion of group X secretory phospholipase A2 (GX KO). These mice have ∼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 A2 (sPLA2), but not a catalytically inactive mutant form of GX sPLA2, significantly reduced steroid production 30–40% in Y1 mouse adrenal cell line. This effect was reversed by the sPLA2 inhibitor, indoxam. Silencing of endogenous M-type receptor expression did not restore steroid production in GX sPLA2-overexpressing Y1 cells, ruling out a role for this sPLA2 receptor in this regulatory process. Expression of steroidogenic acute regulatory protein (StAR), the rate-limiting protein in corticosteroid production, was ∼2-fold higher in adrenal glands of GX KO mice compared with WT mice, whereas StAR expression was suppressed in Y1 cells overexpressing GX sPLA2. Results from StAR-promoter luciferase reporter gene assays indicated that GX sPLA2 antagonizes StAR promoter activity and liver X receptor-mediated StAR promoter activation. In summary, GX sPLA2 is expressed in mouse adrenal glands and functions to negatively regulate corticosteroid synthesis, most likely by negatively regulating StAR expression.