Peroxisome proliferators (PPs) are potent
tumor promoters in rodents. The mechanism of hepatocarcinogenesis requires the
nuclear receptor peroxisome proliferator activated receptor-alpha (
PPARalpha), but might also involve the
PPARalpha independent alteration of signaling pathways that regulate cell growth. Here, we studied the effects of PPs on the
mevalonate pathway, a critical pathway that controls cell proliferation.
Liver X receptors (LXRs) are
nuclear receptors that act as
sterol sensors in the
mevalonate pathway. In gene reporter assays in COS-7 cells, the basal activity of the LXR responsive reporter gene (LXRE-luc) was suppressed by 10 microM
lovastatin and
zaragozic acid A, suggesting that this activity was attributed to the activation of native LXRs, by endogenously produced
mevalonate products. The potent PP and rodent
tumor promoter,
pirinixic acid (WY-14643) also inhibited LXR-mediated transcription in a dose related manner (approximate IC(50) of 100 microM). As did several other PPs including ciprofibric
acid and mono-ethylhexylphthalate. Polyunsaturated and medium to long chain
fatty acids at 100 microM were also potent inhibitors; the
arachidonic acid analogue eicosatetraynoic
acid being the most active (approximate IC(50) of 10 microM). Of the PPs and
fatty acids tested, there was a strong correlation between the ability of these agents to suppress de novo
sterol synthesis in a rat
hepatoma cell line, H4IIEC3, and inhibit LXR-mediated transcription in COS-7 cells, but a discordance between these endpoints and
PPARalpha activation and
fatty acid acyl-CoA oxidase induction. Taken together, these results suggest that PPs and
fatty acids negatively regulate the
mevalonate pathway through a mechanism that is not entirely dependent on
PPARalpha activation. Because of the importance of the
mevalonate pathway in regulating cell proliferation, the modulation of this pathway by PPs and
fatty acids might contribute to their actions on cell growth/differentiation.