title: Peroxisome proliferators and fatty acids negatively regulate liver X receptor-mediated activity and sterol biosynthesis.
abstract: 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.
authors.affiliation: Department of Genetic and Cellular Toxicology, Merck Research Laboratories, WP45-305, West Point, PA 19486, USA. timothy_johnson@merck.com
authors.forename: T E
authors.initials: TE
authors.lastname: Johnson
authors.forename: B J
authors.initials: BJ
authors.lastname: Ledwith
mesh_terms: D042962:Acyl-CoA Oxidase; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins; D005227:Fatty Acids / Q000494:pharmacology*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010088:Oxidoreductases / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000502:physiology; D013261:Sterols / Q000096:biosynthesis*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D005227:Fatty Acids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D013261:Sterols; D014157:Transcription Factors; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase