The steroidogenic acute regulatory (StAR)
protein promotes intramitochondrial delivery of
cholesterol to the
cholesterol side-chain cleavage system, which catalyzes the first enzymatic step in all
steroid synthesis. Intriguingly, substrate
cholesterol derived from
lipoprotein can upregulate StAR gene expression. Moreover, substrate
oxysterols have been suggested to also play a role. To investigate whether
oxysterols can regulate StAR expression, two steroidogenic cell lines, mouse Y1 adrenocortical and MA-10 Leydig
tumor cells, were treated with various
oxysterols and
steroids, including
25-hydroxycholesterol (25 OHC), 22(R)OHC and 20alphaOHC. The majority of these compounds rapidly increased StAR
protein levels within as little as 1 h. The most potent
oxysterols were 20alphaOHC for Y1 and 25 OHC for MA-10 cells. After 8 h, StAR
mRNA abundance also increased whereas there were no detected changes in promoter activity. Thus, in contrast to
lipoprotein,
oxysterols acutely increase StAR
protein levels independently of
mRNA abundance, and later increase
mRNA levels independently of new gene transcription. Therefore, we propose that
oxysterols modulate steroidogenesis at two levels. First,
oxysterols may be important in post-transcriptional regulation of StAR activity and production of
steroids for paracrine action. Secondly, through direct conversion to
steroid,
oxysterols may account in part for StAR-independent
steroid production in the body.