INDUCTION OF THE MAJOR INTEGRAL MEMBRANE-PROTEIN OF MOUSE-LIVER PEROXISOMES BY PEROXISOME PROLIFERATORS

Peroxisome proliferators are known to increase the volume of the peroxisomal compartment in rodent liver. We have examined the induction of the major integral membrane protein of mouse liver peroxisomes (PMP68) by a number of these agents, and compared this with their effect on the peroxisomal bifunctional protein (PBP), an enzyme of the beta-oxidation pathway which is located in the peroxisome matrix. Dietary clofibrate, di-2-(ethylhexyl)phthalate and Wy-14,643, three structurally unrelated proliferators, all increased the mRNA and protein content of PMP68 approx. 2-fold, whereas PBP was induced 8-13-fold. The kinetics and sequence of induction of PMP68 and PBP following a single dose of Wy-14,643 were compared and shown to be similar, and the effects were reversible. Another proliferator, BM 15766, caused maximal induction of PMP68 but only a low induction of PBP; further PBP induction was achieved by the administration of BM 15766 in combination with Wv-14,643. Similarly. BM 15766 and Wy-14,643 increased transcription of the PMP68 gene in vitro. whereas PBP gene transcription was increased by Wv-14,643 but not by BM 15766. Thus peroxisome proliferators enhance the expression of the genes for both the membrane protein PMP68 and the matrix protein PBP, but the regulation of this expression appears to be mediated by different mechanisms.