Zonal heterogeneity of peroxisomal enzymes in rat liver: differential induction by three divergent hypolipidemic drugs.
The hepatic zonation of peroxisomes and four of their matrical enzyme proteins (catalase, acyl coenzyme A oxidase, multifunctional protein, thiolase) has been investigated in normal male rats and after treatment with three divergent hypolipidemic drugs by means of automatic image analysis and quantitative immunoelectron microscopy. The induction of peroxisomal enzymes was confirmed by Western blotting and enzyme activity determinations in liver homogenates and in highly purified peroxisome fractions. In control animals the volume density of peroxisomes and the concentrations of all four enzymes were comparable across the liver acinus. The treatment with all three compounds induced stronger proliferation of peroxisomes in zone 3 than in zone 1 hepatocytes, and significant differences between the different compounds were detectable only in pericentral hepatocytes. The immunolabeling density reflecting the enzyme protein concentration in the peroxisomal matrix was unchanged or reduced for catalase but showed significant elevations for beta-oxidation enzymes in treated animals. It did not increase, however, in parallel with the augmentation of the volume density but showed a different pattern for each enzyme, depending on the acinar location and the type of compound used, suggesting a complex fine regulation for each protein. The total labeling index, reflecting the total amount of each protein, was for almost all enzymes higher in perivenous hepatocytes, indicating that they respond more intensely to hypolipidemic drugs than periportal cells. The elevations of the peroxisomal enzymes in zone 3 of the acinus may contribute to the perturbation of the sterol and bile acid metabolism associated with hypolipidemic therapy.
Lindauer
M
M
Institute for Anatomy and Cell Biology, University of Heidelberg, Federal Republic of Germany.
Beier
K
K
Völkl
A
A
Fahimi
H D
HD
D000101:Acetyl-CoA C-Acetyltransferase / Q000096:biosynthesis; D042962:Acyl-CoA Oxidase; D000818:Animals; D002374:Catalase / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D016253:Microscopy, Immunoelectron; D009097:Multienzyme Complexes / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000960:Hypolipidemic Agents; D009097:Multienzyme Complexes; D010088:Oxidoreductases; D002374:Catalase; D042962:Acyl-CoA Oxidase; D000101:Acetyl-CoA C-Acetyltransferase