Differential effects of lysolipids on steroid synthesis in cells expressing endogenous LPA2 receptor.

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 [ 1 4 C]steroid production in cells preloaded with either [ 1 4 C]cholesterol or [ 1 4 C]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 (LPA 2 ) receptor (with no concomitant changes in the expression of LPA 1 receptor). Expression of LPA 2 is accompanied by LPA-induced sphingosine-1-phosphate (SIP) 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 SIP production. Interestingly, no LPA-induced inhibition of 8Br-cAMP-stimulated progesterone synthesis can be detected in Leydig tumor cell line MA10 cells expressing only LPA 2 receptor. Surprisingly, however, exogenous S1P inhibits agonist-stimulated progesterone in both cell types by inhibiting cyclic AMP accumulation, suggesting different mechanisms of action.