COMPARISON OF DOSE-RESPONSE RELATIONSHIPS FOR INDUCTION OF LIPID METABOLIZING AND GROWTH-REGULATORY GENES BY PEROXISOME PROLIFERATORS IN RAT-LIVER

The regulation of gene expression via the peroxisome proliferator-acti vated receptor (PPAR) is believed to be critical in the effects of per oxisome proliferators on lipid metabolism and possibly in hepatocarcin ogenesis. The involvement of PPAR in the peroxisome proliferator-media ted induction of fatty acid metabolizing genes such as acyl-CoA oxidas e (ACO), fatty acid-binding protein (FABP), and cytochrome P450IVA1 (C YP4A1) has been clearly demonstrated. However, the induction by peroxi some proliferators of important growth regulatory genes such as c-myc has not been investigated extensively. In these studies we examined th e dose-response relationships for the induction of mRNA for the PPAR-r egulated and lipid metabolizing genes AGO, FABP, and CYP4A1 and compar ed them to the immediate early gene c-myc. Liver mRNA from rats fed va rious amounts of the peroxisome proliferator Wy14,643 for 13 weeks was utilized. The lipid metabolism and growth regulatory genes were induc ed by subchronic administration of Wy14,643 but to varying degrees and with different sensitivities. The lowest dose that resulted in a sign ificant change in ACO and FABP expression was 10 ppm. The mRNA for CYP 4A1 and c-myc was significantly affected at the lowest dose examined ( 5 ppm). Also, the maximal induction ranged from 10(5)-fold (CYP4A1) to less than 10-fold (FABP) relative to vehicle-treated animals. The acc umulation of mRNA for AGO, FABP, and CYP4A1, but not c-myc, showed typ ical receptor-mediated dose-response relationships. The effects on gen e expression were compared to rates of hepatic cell proliferation, a p ertinent marker of tumor promotion and hepatocarcinogenesis. Surprisin gly, ACO mRNA showed an excellent correlation (r(2) = 0.9) while c-myc mRNA exhibited a poor correlation (r(2) = 0.3) with cell proliferatio n in rat liver. Although the differences between the dose-response rel ationships of ACO and c-myc mRNA accumulation may suggest immediate ea rly genes are not controlled by PPAR, evidence from PPAR alpha null mi ce support this receptor in both lipid metabolism and growth regulator y genes. This study shows the complexity of responses mediated by pero xisome proliferators, with ACO being a good marker of PPAR-mediated ev ents as well as cell proliferation, while c-myc, a known growth regula tory gene, was induced by Wy14,643 partially via PPAR but did not corr elate well with cell proliferation. (C) 1998 Academic Press.