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PPARalpha-dependent alteration of GRP94 expression in mouse hepatocytes
N Macdonald1, K Barrow, R Tonge
1Cancer Biology Group, Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom.
Biochemical and Biophysical Research Communications
|November 4, 2000
Summary
Peroxisome proliferators (PPs) cause liver tumors in rodents by suppressing apoptosis. Proteomic analysis revealed that PPs upregulate glucose-regulated protein 94 (GRP94), offering new insights into their anti-apoptotic effects.
Area of Science:
- Hepatology
- Toxicology
- Proteomics
Background:
- Peroxisome proliferators (PPs) are rodent hepatocarcinogens.
- PPs induce adverse effects like apoptosis suppression, hepatocyte proliferation, and liver enlargement.
- The peroxisome proliferator-activated receptor alpha (PPARalpha) mediates the response to PPs.
Purpose of the Study:
- To identify molecular pathways underlying the adverse effects of PPs.
- To investigate the role of PPARalpha in PP-mediated hepatocarcinogenesis.
Main Methods:
- Proteomic analysis of PP-treated hepatocytes from wild-type and PPARalpha-null mice.
- Two-dimensional (2D) silver-stained gel electrophoresis.
- Western blotting analysis.
Main Results:
- Eighteen protein spots showed differential expression in PP-treated wild-type hepatocytes.
- Proteins involved in lipid metabolism and ATP synthase beta subunit were identified.
- Glucose-regulated protein 94 (GRP94) was consistently overexpressed upon PP stimulation.
Conclusions:
- PPs exert adverse effects through PPARalpha-mediated pathways.
- GRP94 overexpression contributes to the anti-apoptotic mechanism of PPs.
- These findings provide novel insights into PP-induced hepatocarcinogenesis.