Decreased hepatic production of very low density lipoproteins following activation of fatty acid oxidation by Ro 22-0654

In fed rat livers perfused with (l-'*C)oleic acid, Ro 22-0654 (4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride), an inhibitor of fatty acid synthesis, acti- vated ketogenesis and decreased the secretion of triglyceride in very low density lipoproteins (VLDL). Ro 22-0654 was without effect on total oleic acid uptake and utilization by the liver. The liver triglyceride content, urea synthesis, and bile production were also unaffected. Ro 22-0654 increased the conversion of both exogenous and endogenous fatty acid substrates to ketone bodies, while decreasing the secretion of triglyceride synthesized from both of these sources. Depressed fatty acid synthesis ac- counted for a relatively small portion of the decrease in secretory triglyceride derived from endogenous sources. '4C0, from (1-"C)oleic acid was unchanged by Ro 22-0654. This drug de- creased the malonyl-CoA content of rat liver freeze-clamped in vivo, providing an explicable mechanism for its activation of fatty acid oxidation. Hepatic citrate was also diminished. The present studies indicate the following sequence of events in the liver of fed rats following the administration of Ro 22-0654: decreased formation of citrate and malonyl-CoA, decreased fatty acid synthesis via decreased carbon supply and increased fatty acid oxidation via stimulation of acylcarnitine formation, decreased synthesis of triglyceride from both endogenous and exogenous fatty acids, resulting in the decreased formation and secretion of VLDL. - Yamamoto, M., N. Fukuda, J. Triscari, A. C. Sullivan, and J. A. Ontko. Decreased hepatic production of very low density lipoproteins following activation of fatty acid oxidation by Ro 22-0654. J. Lipid 1985. 26: 1196-1204. liver is a key determinant of plasma lipid concentrations. Our previous studies on the regulation of VLDL production have examined metabolic and genetic condi- tions characterized by the hypersecretion of VLDL particles (5-9). Multiple effects of 5-tetradecyloxy-2- furoic acid (TOFA) in the perfused liver, culminating in decreased hepatic triglyceride and cholesterol secretion, were also investigated (10). We now report depression of hepatic VLDL production by the drug R o 22-0654 (Fig. l), an inhibitor of fatty acid synthesis (ll), and definition of underlying alterations in hepatocellular fatty acid metabolism. This agent decreased hepatic triglyceride secretion without concurrent accumulation of lipids in the liver. Results implicate activation of hepatic ketogenesis as a major event in the sequence of metabolic alterations.