In vitro evidence for involvement of CoA thioesters in peroxisome proliferation and hypolipidaemia.
The mechanisms of peroxisomal induction and hypolipidaemia caused by treatment with peroxisome proliferators, such as nafenopin and clofibrate, remain to be elucidated. Proposed mechanisms include receptor-mediated processes or adaptations resulting from disruption of hepatic lipid metabolism. The latter mechanism was investigated in a series of in vitro studies. Incubation of primary rat hepatocytes with various carboxyl-containing compounds revealed no clear common factor which imparted potency as a peroxisomal inducer. Inhibitors of fatty acyl-CoA synthetase, norepinephrine and desulpho-CoA, however, decreased the level of peroxisomal induction by nafenopin in rat hepatocytes, suggesting that activation of carboxyl-containing compounds to their CoA thioesters may be a necessary step in initiating peroxisome proliferation. Coenzyme A thioesters of nafenopin, clofibric acid and other carboxyl-containing chemicals were synthesised and found to inhibit the activity of acetyl-CoA carboxylase to varying degrees. The CoA thioester of nafenopin was the most potent inhibitor among this group (Ki = 1.45 x 10(-5) M), but weaker than palmitoyl-CoA (Ki = 2.22 x 10(-6) M), the feedback inhibitor of acetyl-CoA carboxylase. Hypolipidaemia caused by treatment with peroxisome proliferators may, therefore, be related to inhibition of fatty-acid synthesis by the corresponding CoA thioester derivative.
Tomaszewski
K E
KE
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Melnick
R L
RL
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003065:Coenzyme A / Q000494:pharmacology; D004952:Esters / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008830:Microbodies / Q000187:drug effects*; D009255:Nafenopin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats
D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D004952:Esters; D005227:Fatty Acids; D009255:Nafenopin; C051513:clofibric acid-coenzyme A; C051515:nafenopin-coenzyme A; D002995:Clofibric Acid; C035999:desulfo-coenzyme A; D000103:Acetyl-CoA Carboxylase; D003065:Coenzyme A; D009638:Norepinephrine