Journal of Lipid Research, Vol 26, 1196-1204, Copyright © 1985 by Lipid Research, Inc.
Decreased hepatic production of very low density lipoproteins following activation of fatty acid oxidation by Ro 22-0654
M Yamamoto, N Fukuda, J Triscari, AC Sullivan and JA Ontko
In fed rat livers perfused with [1-14C]oleic acid, Ro 22-0654 (4-amino-
5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride), an
inhibitor of fatty acid synthesis, activated 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 accounted for a relatively small
portion of the decrease in secretory triglyceride derived from endogenous
sources. 14CO2 from [1-14C]oleic acid was unchanged by Ro 22-0654. This
drug decreased 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.
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