The interplay between bioactive sphingolipids and steroid hormones

Abstract

Steroid hormones regulate various physiological processes including development, reproduction, and metabolism. These regulatory molecules are synthesized from cholesterol in endocrine organs - such as the adrenal glands and gonads - via a multi-step enzymatic process that is catalyzed by the cytochrome P450 superfamily of monooxygenases and hydroxysteroid dehydrogenases. Steroidogenesis is induced by trophic peptide hormones primarily via the activation of a cAMP/protein kinase A (PKA)-dependent pathway. However, other signaling molecules, including cytokines and growth factors, control the steroid hormone biosynthetic pathway. More recently, sphingolipids, including ceramide, sphingosine-1-phosphate, and sphingosine, have been found to modulate steroid hormone secretion at multiple levels. In this review, we provide a brief overview of the mechanisms by which sphingolipids regulate steroidogenesis. In addition, we discuss how steroid hormones control sphingolipid metabolism. Finally, we outline evidence supporting the emerging role of bioactive sphingolipids in various nuclear processes and discuss a role for nuclear sphingolipid metabolism in the control of gene transcription.

Figure 1

Steroid hormone biosynthetic pathways. Diagram representing the sequential metabolism of cholesterol into the major steroid hormones in the adrenal cortex (square) and gonads (circle). The steroidogenic gene responsible for each enzymatic reaction is indicated above the arrow. CYP11A1 (encodes P450scc); CYP17 (encodes P450c17α); 3β-HSD (encodes 3β hydroxysteroid dehydrogenase); CYP21 (encodes P450c21); CYP11B1 (encodes P45011β); CYP11B2 (encodes aldosterone synthase); CYP19 (encodes aromatase); 17α-HSD (encodes 17α hydroxysteroid dehydrogenase).

Figure 2

Overview of the sphingolipid metabolic pathway. Ceramide (cer) is central to sphingolipid metabolism and can be generated via de novo biosynthesis, through the degradation of complex sphingolipids, or by the recycling of sphingosine. Degradation of ceramide leads to the formation of sphingosine and sphingosine-1-phosphate (S1P). Abbreviations: serine palmitoyltransferase (SPT), ceramide (cer), ceramide kinase (CK), sphingomyelin (SM), sphingomyelinase (SMase), sphingomyelin synthase (SM synthase), sphingosine kinase (SK), sphingosine-1-phosphate (S1P).

Figure 3

The structural similarities of ceramide (CER), sphingosine (SPH), and sphingosine-1-phosphate (S1P) and their established roles in steroid hormone production. Although these lipids are structurally similar, they have unique roles in cellular function. CER functions as an intracellular second messenger to suppress progesterone and testosterone biosynthesis while S1P acts primarily via binding to cell-membrane S1P receptors to induce cortisol and aldosterone production. SPH binds to and antagonizes the function of steroidogenic factor 1 (SF-1). Abbreviations: Steroidogenic acute regulatory protein (StAR); cytochrome P450 17α-hydroxylase (P450c17α); cytochrome P450 aromatase (P450arom); 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); prostaglandin E2 (PGE₂); liver receptor homologue-1 (LRH-1).