Endocrine Abstracts

In addition to their documented impact on the cardiovascular system, polyunsaturated fatty acids (PUFAs) have also been shown to modulate steroidogenesis. However, the mechanistic nature of PUFA action on steroid synthesis remains unknown. PUFAs are recognised modulators of cholesterol trafficking. Liver X receptor (LXR) is a known cholesterol sensor that regulates a range of genes involved in cholesterol metabolism including Steroidogenic acute regulatory protein (StAR) which is involved in the transfer of cholesterol across the mitochondrial membrane in steroidogenic cells. Therefore we have investigated the hypothesis that PUFAs stimulate steroidogenesis through affecting expression of LXR which in turn modulates the expression of StAR.

The mouse adrenocortical Y1 cell line was used to assess the effects of n-3 PUFAs and/or LXR agonist T1317 on protein (western blotting) expression for LXR and StAR as well as steroid production (pregnenolone by specific RIA).

Treatment with a range of n-3 PUFAs (including eicosapentaenoic acid: EPA; 100 μM) for upto 24 h resulted in a significant increase in steroid output, associated with increased expression of StAR protein, without apparent changes in LXR protein. In contrast, when treated with T1317 alone (1 and 10 μM) steroid production was significantly decreased, despite an apparent increase in StAR protein expression. When the interaction between PUFAs and T1317 was assessed (10 μM T1317, 100 μM PUFA, for 24 h) steroid output was significantly decreased implying that the stimulatory effect of PUFA could not overcome the inhibitory effects of the LXR agonist, T1317. As LXR regulates a number of genes involved in cholesterol efflux it is possible that decreased steroidogenesis may be mediated by a decline in substrate availability as a result of cholesterol movement out of the cells.

Hence, we conclude that PUFAs mediate increased steroid production through increased StAR protein expression and not through changed LXR protein expression. Work supported by BBSRC.