Abstract
Incubation of ovarian luteal cells with the bioactive lipid mediator lysophosphatidic acid (LPA) for 180 min abolishes gonadotropin-induced steroid production with no attenuation of the cyclic AMP accumulation. Treatment with the lysolipid also diminishes [14C]steroid production in cells preloaded with either [14C]cholesterol or [14C]acetate. Neither the expression of steroidogenic acute regulatory (StAR) protein nor in vitro steroid synthesis is affected in isolated mitochondrial fractions. The LPA-induced attenuation of steroid production occurs only in the mid-cycle corpus luteum and is associated with a transient endogenous expression of mRNA for the lysophosphatidic acid A2 (LPA2) receptor (with no concomitant changes in the expression of LPA1 receptor). Expression of LPA2 is accompanied by LPA-induced sphingosine-1-phosphate (S1P) production. Because luteal cells, in the presence of the sphingosine kinase inhibitor dihydrosphingosine, can overcome the inhibitory effects of LPA on steroid synthesis, we suggest the possible requirement of intracellular S1P production. Interestingly, no LPA-induced inhibition of 8Br-cAMP-stimulated progesterone synthesis can be detected in Leydig tumor cell line MA10 cells expressing only LPA2 receptor. Surprisingly, however, exogenous S1P inhibits agonist-stimulated progesterone in both cell types by inhibiting cyclic AMP accumulation, suggesting different mechanisms of action.
Highlights
Incubation of ovarian luteal cells with the bioactive lipid mediator lysophosphatidic acid (LPA) for 180 min abolishes gonadotropin-induced steroid production with no attenuation of the cyclic AMP accumulation
Bioactive lipid molecules signal through their cognate G-protein-coupled receptors, which belong to a growing family of lipid binding receptors previously named endothelial differentiation genes (Edgs) and renamed lysophosphatidic acid receptors A1 (LPA1), A2 (LPA2), and A3 (LPA3) according to the International Union of Pharmacology nomenclature system [6]
We studied here LPA receptor-mediated effects on steroid synthesis and observed that LPA inhibited gonadotropin, luteinizing hormone (LH)-induced steroidogenesis in ovarian luteal cells
Summary
Incubation of ovarian luteal cells with the bioactive lipid mediator lysophosphatidic acid (LPA) for 180 min abolishes gonadotropin-induced steroid production with no attenuation of the cyclic AMP accumulation. The LPA-induced attenuation of steroid production occurs only in the mid-cycle corpus luteum and is associated with a transient endogenous expression of mRNA for the lysophosphatidic acid A2 (LPA2) receptor (with no concomitant changes in the expression of LPA1 receptor). Expression of LPA2 is accompanied by LPA-induced sphingosine-1-phosphate (S1P) production. In the presence of the sphingosine kinase inhibitor dihydrosphingosine, can overcome the inhibitory effects of LPA on steroid synthesis, we suggest the possible requirement of intracellular S1P production. Differential effects of lysolipids on steroid synthesis in cells expressing endogenous LPA2 receptor. Some mammalian cells express only one LPA receptor form, whereas other cells spatially or temporally coexpress more than one receptor subtype [1]
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