title: Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor.
abstract: Adrenocorticotropin (ACTH) signaling increases glucocorticoid production by promoting the interaction of transcription factors and coactivator proteins with the promoter of steroidogenic genes. The nuclear receptor steroidogenic factor 1 (SF-1) is essential for steroidogenic gene transcription. Sphingosine (SPH) is a ligand for SF-1. Moreover, suppression of expression of acid ceramidase (ASAH1), an enzyme that produces SPH, increases the transcription of multiple steroidogenic genes. Given that SF-1 is a nuclear protein, we sought to define the molecular mechanisms by which ASAH1 regulates SF-1 function. We show that ASAH1 is localized in the nuclei of H295R adrenocortical cells and that cyclic AMP (cAMP) signaling promotes nuclear sphingolipid metabolism in an ASAH1-dependent manner. ASAH1 suppresses SF-1 activity by directly interacting with the receptor. Chromatin immunoprecipitation (ChIP) assays revealed that ASAH1 is recruited to the promoter of various SF-1 target genes and that ASAH1 and SF-1 colocalize on the same promoter region of the CYP17A1 and steroidogenic acute regulatory protein (StAR) genes. Taken together, these results demonstrate that ASAH1 is a novel coregulatory protein that represses SF-1 function by directly binding to the receptor on SF-1 target gene promoters and identify a key role for nuclear lipid metabolism in regulating gene transcription.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Lucki
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
authors.forename: Sibali
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Elaine
authors.initials: E
authors.lastname: Wang
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Marion B
authors.initials: MB
authors.lastname: Sewer
mesh_terms: D055573:Acid Ceramidase / Q000378:metabolism*; D000302:Adrenal Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D004268:DNA-Binding Proteins; C515057:NR5A1 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D013107:Sphingolipids; D054339:Steroidogenic Factor 1; D000098682:Steroidogenic Acute Regulatory Protein; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C526693:ASAH1 protein, human; D055573:Acid Ceramidase; D013110:Sphingosine