Altered hepatic metabolism of free fatty acids underlying hypersecretion of very low density lipoproteins in the genetically obese Zucker rats.

Abstract

condition.This hyperlipidemia appears to be caused by increased production of triglyceride-rich lipoproteins by the liver rather than by defective mechanisms for the removal of these lipoproteins from the circulation.The lipoprotein lipase activities in the tissues of the mature obese Zucker rat are not depressed (4, 5), indicating that this determinant of the removal process is unimpaired.The studies of Schonfeld and Pfleger (6), who observed greater accumulation of triglyceride in recirculating perfusates of livers from obese Zucker rats, suggest that overproduction of triglyceride-rich lipoproteins is involved in the genesis of the characteristic hyperlipemia.Increased triglyceride secretion may be a consequence of increased hepatic lipogenesis, observed in these animals by Martin (7) and Sullivan et al. (8).Alternatively, or additionally, it may be derived from an altered hepatic metabolism of free fatty acids.Thus, a selective decrease in the oxidation of long chain fatty acids by the liver consequently increases triglyceride synthesis and leads to the hypersecretion of triglyceride-rich lipoproteins (9).A direct effect on the esterification process may also participate.In the present study, the metabolism of oleic acid by isolated perfused intact livers from lean and obese Zucker rats was compared in a detailed examination of the concurrent processes of fatty acid oxidation, esterification, and lipoprotein production.Achievement of the steady metabolic state in the intact organ during the constant infusion of fatty acid substrate was evidenced by a constant rate of accumulation of ketone bodies and secretory lipoproteins in the perfusion medium.These studies have provided an integrated picture of the metabolic alterations in the intracellular utilization of fatty acids and in the consequent production of triglyceriderich Iipoproteins by the liver of the genetically obese Zucker rat.These observations accordingly suggest events underlying the development and maintenance of the hyperlipemic state in these animals.Some of this work has been reported in a preliminary communication (10).EXPERIMENTAL PROCEDURES Animals-Male lean and obese littermate Zucker rats were obtained from Hoffmann-La Roche, housed individually (room temperature, 22 "C), and allowed free access to Purina laboratory chow and water.Lighting was controlled (6 a.m.4 p.m., light; 6 p.m.4 a.m., dark).Between 9:OO and 9:30 a.m., rats were anesthetized (9).Blood was obtained by heart puncture just before inserting a cannula into the portal vein.Livers were removed for perfusion.Stomachs were weighed to provide an index of food consumption.Blood was allowed to clot for 5 h at 5 "C.Serum was separated by centrifugation at 3000 rpm for 30 min at 5 "C.Liver Perfusion-The perfusion equipment and procedures were those employed and described in part, previously (9).This recirculating perfusion system includes the following components in series: ( a ) a water-jacketed cylindrical Plexiglas reservoir to maintain the per-14066