Isolated hepatocytes were prepared from meal-fed female Wistar rats to determine the effects of various substrates on ketogenesis, fatty acid synthesis and glycolysis.
Inhibition of fatty acid synthesis with dibutyryl cyclic AMP or oleate resulted in increased ketogenesis. On the other hand, octanoate, which is transported by a carnitine independent mechanism into the mitochondrion, showed marked ketogenesis without any effect on fatty acid synthesis. Acetate, which is converted to acetyl-CoA either in cytosol or in mitosol, increased both ketogenesis and fatty acid synthesis. These data indicated that there is not always a reciprocal relationship between ketogenesis and fatty acid synthesis.
Exogenous lactate and pyruvate relieved the enhanced ketogenesis with octanoate in association with increase of fatty acid synthesis and CO₂ formation from octanoate. It was concluded that the flow of acetyl groups in fatty acid synthesis contributed more than CO2 formation in the reduction of ketogenesis by exogenous lactate and pyruvate.
The present data suggest that there is a regulatory link between fatty acid synthesis and ketogenesis. Generally, insufficient activity of fatty acid synthesis permits a large increase in ketogenesis, partly because entry of long-chain fatty acyl-CoA into the mitochondrion is facilitated and partly because utilization of acetyl groups is decreased.
Chylomicrons and their remnants prepared in vivo showed a specific inhibitory effect on fatty acid synthesis without any modulation of ketogenesis. This metabolic effect is very difficult to explain and the mechanism is now under investigation in our laboratory. Chylomicron remnants prepared in vitro were found to release free fatty acids into the medium, probably because of bound lipoprotein lipase activity. Metabolic effects of in vitro remnants can evidently be attributed to released free fatty acids.