INCREASED SECRETION OF TRIGLYCERIDE AND CHOLESTEROL FOLLOWING INHIBITION OF LONG-CHAIN FATTY-ACID OXIDATION IN RAT-LIVER

The effects of emeriamine, a fungal metabolite and a potent inhibitor of mitochondrial fatty acid oxidation, on ketogenesis and lipid secret ion were examined in isolated perfused livers from 2-day-fasted rats. Liver perfusion with increasing concentrations of emeriamine up to 3 m u mol caused a dose-dependent inhibition of ketone body production. Th e hepatic uptake of exogenous oleic acid substrate was comparable in t he control and emeriamine-treated livers. The addition of 2 mu mol eme riamine to the perfusion medium at either the beginning of perfusion o r 2 h later caused immediate and almost complete cessation of ketone b ody production, which was accompanied by a concomitant decrease in the beta-hydroxybutyrate:acetoacetate ratio, suggesting a decreased produ ction of NADH via mitochondrial beta-oxidation. Conversely, both trigl yceride and cholesterol secretions were elevated, indicating a recipro cal response in ketogenesis and lipid secretion by the livers. The pro portion of oleate in the perfusate triglyceride obtained from emeriami ne-treated livers was significantly higher than that from control live rs. In the post-perfused liver triglyceride, oleate was progressively increased in the livers treated with the inhibitor 2 h after perfusion and at the beginning of perfusion, respectively. These results indica te that direct inhibition of fatty acid oxidation diverts the exogenou s fatty acids to the esterification pathway, and subsequently stimulat e the synthesis and secretion of triglyceride and cholesterol. The fat ty acid oxidation rate in the liver is, therefore, a critical determin ant for the synthesis and secretion of these lipid components.