UTILIZATION AND PREFERRED METABOLIC PATHWAY OF KETONE-BODIES FOR LIPID-SYNTHESIS BY ISOLATED RAT HEPATOMA-CELLS

Morris hepatoma 7777 cells freshly isolated from highly malignant tumors grown in the hindlimb of buffalo rats actively convert ketone bodies to cholesterol and fatty acids. On the basis of results obtained with (-)-hydroxycitrate, an inhibitor of the ATP citrate lyase enzyme, the metabolic pathway for acetoacetate conversion to lipids is exclusively cytoplasmic, whereas that for 3-hydroxybutyrate involves both extra- and intramitochondrial compartments. Subcellular distribution studies indicated accumulation and compartmentation of 3-hydroxybutyryl CoA primarily in the cytoplasm of hepatoma cells incubated with either ketone body. In contrast, the compartmentation of acetoacetyl CoA is dependent on whether the substrate is acetoacetate or 3-hydroxybutyrate. With acetoacetate, the acetoacetyl CoA is entirely cytoplasmic, whereas with 3-hydroxybutyrate, it is equally divided between the intra- and extramitochondrial compartments. The results are discussed in terms of the known and proposed metabolic pathways for lipid synthesis from ketone bodies, particularly that from 3-hydroxybutyrate.