ACTIVATION OF A PEROXISOME-PROLIFERATING CATABOLITE OF CHOLIC-ACID TOITS COA ESTER

We have shown that a microbial cholic acid catabolite 4,6,6abeta,7,8,9 ,9aalpha,9bbeta-decahydro-6abeta-m yl-3-oxo-1H-cyclopenta[f]quinolin-7 beta-yl)valeric acid (DCQVA), is a potent peroxisome proliferator. In this paper a possible key stage in DCQVA metabolism, the activation of DCQVA to its CoA ester, has been investigated in rat liver microsomes and particulate fractions. The microsomal reaction was dependent on C oA, ATP, DCQVA (0.2-1 mM) and protein content. The reaction was decrea sed by storage at 4-degrees-C, preincubation of microsomes at 37-degre es-C for 5 min, or inclusion of Triton X-100 in the reaction mixture. Such treatments also enhanced generation of long-chain fatty acyl-CoAs , as determined by h.p.l.c. analysis. The same effect was caused by ex posing the microsomes to phospholipase A2, suggesting that endogenous fatty acids may compete with DCQVA for esterification with CoA. Subcel lular fractionation of rat liver demonstrated that the activity of DCQ VA-COA synthesis was localized predominantly in the microsomal fractio n, in contrast to long-chain fatty acyl-CoA synthetase, which was dist ributed among all particulate fractions. Administration of clofibrate of rats did not affect the distribution of DCQVA-CoA synthesis activit y. In contrast to a 2-fold induction of long-chain fatty acyl-CoA synt hetase by clofibrate treatment, the activity of DCQVA-CoA synthesis in the microsomal fraction decreased by 80%. These results suggest that DCQVA is activated by an enzyme distinct from long-chain fatty acyl-Co A synthetase. The resulting perturbation of fatty acid metabolism may be involved in the mechanism whereby DCQVA causes peroxisome prolifera tion.