Xj. Wang et al., The role of arachidonic acid in steroidogenesis and steroidogenic acute regulatory (StAR) gene and protein expression, J BIOL CHEM, 275(26), 2000, pp. 20204-20209
This study was conducted to examine the mechanism for arachidonic acid (AA)
regulation of steroidogenic acute regulatory (StAR) protein expression and
the relationship between AA and cAMP in hormone-induced steroidogenesis, D
ibutyryl cyclic AMP (Bt(2)cAMP)-stimulated MA-10 Leydig cells were treated
with AA and/or the phospholipase A, inhibitor, dexamethasone, Dexamethasone
significantly reduced Bt(2)cAMP-stimulated progesterone production, StAR p
romoter activity, StAR mRNA, and StAR protein. The inhibitory effects of de
xamethasone were reversed by the addition of 150 mu M AA to MA-10 cells. In
addition, MA-10 cells were treated with the lipoxygenase inhibitor, nordih
ydroguaiaretic acid (NDGA), the 5-lipoxygenase inhibitor, AA861, the epoxyg
enase inhibitor, miconazole, and the cyclooxygenase inhibitor, indomethacin
, Both NDGA and AA861 inhibited progesterone production and StAR protein ex
pression. AA861-inhibited progesterone synthesis and StAR protein were part
ially reversed by addition of the 5-lipoxygenase metabolite, 5(S)-hydropero
xy-(6E,8Z,11Z, 14Z)-eicosatetraenoic acid. Inhibition of epoxygenase activi
ty inhibited progesterone production significantly, but StAR protein was on
ly slightly reduced. Indomethacin enhanced StAR protein expression and sign
ificantly increased progesterone production. Inhibition of AA release or li
poxygenase activities did not affect protein kinase A activity, whereas inh
ibition of protein kinase A activity using H89 reduced Bt(2)cAMP-induced St
AR protein. AA alone did not induce StAR protein expression nor steroid pro
duction. These results demonstrate the essential role of AA in steroid bios
ynthesis and StAR gene transcription and suggest the possible involvement o
f the lipoxygenase pathway in steroidogenesis. This study further indicates
that AA and cAMP transduce signals from trophic hormone receptors to the n
ucleus through two separate pathways and act to co-regulate steroid product
ion and StAR gene expression and indicates that both pathways are required
for trophic hormone-stimulated steroidogenesis.