PPAR alpha-dependent alteration of GRP94 expression in mouse hepatocytes

The adverse effects of the peroxisome proliferators (PPs), a class of roden t nongenotoxic hepatocarcinogens, include suppression of apoptosis, inducti on of hepatocyte proliferation, and liver enlargement which eventually lead s to tumours, The response to PPs is mediated by the peroxisome proliferato r activated receptor alpha (PPAR alpha), We carried out proteomic analyses of PP-treated hepatocytes from wild-type and PPAR alpha -null mice to ident ify the molecular pathways underlying the adverse effects of PPs, We have i dentified eighteen protein spots exhibiting differential expression in PP-t reated wild-type mouse hepatocytes, Several proteins involved in lipid meta bolism pathways, but also ATP synthase beta subunit, which are regulated by PPs were identified. In addition, both 2D silver-stained gels and Western blotting analysis indicated that the anti-apoptotic glucose-regulated prote in 94 (GRP94) is consistently overexpressed upon stimulation with PPs, prov iding us with novel insights into the anti-apoptotic mechanism activated by PPs. (C) 2000 Academic Press.