THE EFFECT OF RETINOIDS AND CLOFIBRIC ACID ON THE PEROXISOMAL OXIDATION OF PALMITIC ACID AND OF 3-ALPHA,7-ALPHA,12-ALPHA-TRIHYDROXY-5-BETA-CHOLESTANOIC ACID IN RAT AND RABBIT HEPATOCYTES

The effects of retinoids and the peroxisome proliferator clofibric acid on peroxisomal enzyme pathways were studied in hepatocytes from both rat and rabbit. Retinoic acid and retinol increased the activity of acyl-CoA oxidase in rabbit hepatocytes around 60% and around 30% in rat hepatocytes. Exposure to clofibric acid caused an increase in acyl-CoA oxidase activity of 115% in rat hepatocytes and of 40% in rabbit hepatocytes, indicating that rabbit is less sensitive to peroxisome proliferator than rat. Simultaneous exposure to clofibric acid and retinoids did not act additatively or synergistically. Both rabbit and rat hepatocytes expressed mRNA for the peroxisome proliferator activated receptor, (PPAR), although the transcript in rabbit was slightly smaller compared to that expressed in rat hepatocytes. The effect of retinoic acid in 7800 C1 Morris rat hepatoma cells, a cell line known to have an inducible peroxisomal beta-oxidation of fatty acids, was only slight with an increase of the acyl-CoA oxidase activity of 25% compared with control cells. As for clofibric acid, which gave a 2-fold induction of the acyl-CoA oxidase activity, the effect of retinoic acid was potentiated by dexamethasone. These cells also expressed mRNA for PPAR, with the same size as that found in rat hepatocytes. The oxidation of 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid (THCA), an intermediate in bile acid formation, in rat hepatocytes increased 110% by clofibric acid and around 80% by retinoic acid. In rabbit hepatocytes, clofibric acid increased the oxidation rate 75% and retinoic acid 100%. The results presented here show similarities in the effects of retinoids and clofibric acid on the acyl-CoA oxidase activity and the oxidation rate of THCA, since they increase these two peroxisomal activities in hepatocytes in vitro. A decrease in both these enzyme activities occurs during cultivation time in untreated primary hepatocyte cultures. The present data may therefore either be explained by an increased expression or an induced stability of the enzymes involved.