Effect of clofibrate treatment on hepatic prostaglandin catabolism and action.
Prostaglandins (PG) modulate hepatocyte glucose and lipid metabolism. Hepatocytes rapidly metabolize PG via beta-oxidation, terminating PG action. Clofibrate induces hepatic peroxisomal beta-oxidative activity, for which PG are substrates. To determine the effect of clofibrate-treatment on liver PG metabolism and action, hepatocytes were isolated from rats maintained on a control or clofibrate-supplemented (0.5%) diet for 7 to 9 days. Rates of PG catabolism were determined by high performance liquid chromatography resolution of [3H]PG from [3H]metabolites. Clofibrate treatment enhanced the rates of PGE2, PGF2, and PGD2 degradation by 85%, 278% and 137%, respectively. Rates of PG degradation were correlated with hepatocyte carnitine acetyltransferase activity, a marker of peroxisomal proliferation. Further evidence of enhanced hepatocyte peroxisomal beta-oxidation of PG after clofibrate-treatment was obtained by confirming loss of the 1-position carbon from [1-14C]PGE2 during PGE2 metabolism and failure of the carnitine acyltransferase inhibitor acetyl-DL-aminocarnitine to inhibit PGE2 metabolism. Associated with the faster degradation of PGE2 by hepatocytes from clofibrate-treated rats was loss of inhibition of hepatocyte glucagon-stimulated glycogenolysis by exogenous PGE2. Thus, clofibrate's induction of peroxisomal beta-oxidation is associated with accelerated catabolism of PG and decreased PG action. Alterations in PG breakdown provide a mechanism for modulating hepatic PG effects.
Brass
E P
EP
Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
Ruff
L J
LJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002994:Clofibrate / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D010168:Palmitates; D011453:Prostaglandins; D006003:Glycogen; D002994:Clofibrate; D015232:Dinoprostone