Triglyceride accumulation by peroxisome proliferators in rat hepatocytes.
Peroxisome proliferators (PxPs) induce peroxisomal beta-oxidation (Px-ox) in the liver of rodents and have a hypolipidemic function. To investigate hypolipidemic effect of PxPs, the relationship between TG fluctuation and Px-ox activity, as an indicator of the function of PxPs, was studied in primary cultured rat hepatocytes. Nafenopin (Nf) treatment of hepatocytes caused an increase in Px-ox activity in association with cellular TG accumulation in a time-dependent manner with a coefficient of r=0.918. This relationship between the activity and cellular TG were obtained using structurally diverse PxPs with a correlation coefficient of r=0.747. Treatment of the hypolipidemic drug, but non-PxP Pravastatin, decreased TG in the medium, but did not have the effects on cellular TG and Px-ox activity. The total amount of TG and diacylglycerol acyltransferase activity, the last enzyme in the TG de novo synthesis pathway, were not affected by Nf treatment. When hepatocytes were cultured with Brefeldin A, cellular TG was accumulated, the same as with Nf, however, Px-ox activity was not enhanced. Nf treatment markedly decreased the level of apolipoprotein B (apo B) in very low density lipoprotein (VLDL) fractions prepared from conditioned media and increased that of cellular apoB by Western blot analysis. Microsomal triglyceride transfer protein activity was not influenced by Nf. Together, with regards to TG lowering effect of PxPs, it is suggested that PxPs cause hepatocellular accumulation of TG without effects on TG biosynthesis and VLDL construction, and they might have inhibitory effect on VLDL secretion process.
Kawano
Hiroko
H
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan. kawano@pharm.kobegakuin.ac.jp
Nagata
Tomomi
T
Narahara
Masanori
M
Kanazawa
Michiko
M
Miyake
Masaharu
M
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009255:Nafenopin / Q000494:pharmacology; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000096:biosynthesis*
D001055:Apolipoproteins B; D017077:Culture Media, Conditioned; D000960:Hypolipidemic Agents; D020025:Peroxisome Proliferators; D014280:Triglycerides; D009255:Nafenopin