Characterization of the role of acid ceramidase in adrenocortical steroid hormone biosynthesis

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Title: Characterization of the role of acid ceramidase in adrenocortical steroid hormone biosynthesis
Author: Lucki, Natasha Chrystman
Abstract: Sphingolipids modulate multiple cellular functions, including steroid hormone biosynthesis. Sphingosine is an antagonist ligand for the nuclear receptor steroidogenic factor 1 (SF-1), which is the primary transcriptional regulator of most steroidogenic genes. Furthermore, sphingosine-dependent repression of SF-1 function is dependent on the expression of acid ceramidase (ASAH1), an enzyme that forms sphingosine. Based on these data, I hypothesized that ACTH/cAMP signaling regulates ASAH1 function at both transcriptional and post-transcriptional levels. In addition, because SF-1 is predominantly a nuclear protein, I postulated that ASAH1 modulates SF-1 function and, therefore, steroidogenic gene expression by controlling the nuclear concentrations of SPH. To test these hypotheses, I first examined the effect of chronic ACTH/cAMP signaling on the transcription of the ASAH1 gene. Next, the functional significance of ASAH1 expression in adrenocortical cells was probed by generating an ASAH1-knockdown cell line. I subsequently characterized the role of ASAH1 as a transcriptional nuclear receptor coregulator. Finally, I defined the role of sphingosine-1-phosphate, a bi-product of ASAH1 activity, in the acute phase of cortisol biosynthesis. Using a variety of experimental approaches, I identified cAMP response element binding protein as an essential transcriptional activator of the ASAH1 gene. Analysis of adrenocortical cells lacking ASAH1 revealed that ASAH1 is a global regulator of steroidogenic capacity. Furthermore, I identified ASAH1 as a nuclear protein and defined the molecular determinants of the interaction between ASAH1 and SF-1. Collectively, this body of work establishes the integral role of ASAH1 in the regulation of ACTH-dependent adrenocortical cortisol biosynthesis.
Type: Dissertation
URI: http://hdl.handle.net/1853/42804
Date: 2011-11-14
Publisher: Georgia Institute of Technology
Subject: Steroidogenic factor 1
Acid ceramidase
Sphingolipid
Adrenal gland
Cortisol
Sphingosine
Adrenal cortex
Adrenocortical hormones
Steroid hormones
Glycosphingolipids
Department: Biology
Advisor: Committee Chair: Sewer, Marion; Committee Co-Chair: Merrill, Al; Committee Member: Boyan, Barbara; Committee Member: Fan, Yuhong; Committee Member: McCarty, Nael
Degree: PhD

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