The Regulation of Hepatic Triglyceride Metabolism by Free Fatty Acids

Abstract Livers from normal fed male rats were perfused in vitro with equimolar quantities of either caproic, caprylic, lauric, palmitic, stearic, oleic, linoleic, or linolenic acid. The concentration of free fatty acid in the medium was maintained at approximately 0.5 mm by constant infusion of the fatty acid during the experimental period of 4 hours. The rate of uptake of free fatty acid by the liver, about 13.2 µmoles per g of liver per hour, was similar for all fatty acids. The total output of triglyceride by the liver, however, was a function of the chemical structure of the specific fatty acid infused. The secretion of triglyceride into the medium and the accumulation of triglyceride by the liver was not stimulated by infusion of either caproic or caprylic acids. The output of triglyceride by the liver after 4 hours of perfusion was observed to be proportional to the number of carbon atoms in the saturated fatty acid; when long chain fatty acids containing 18 carbon atoms were infused, the output of triglyceride decreased as the number of double bonds in the fatty acid increased. These effects of the fatty acid substrate were not clearly apparent after perfusion for shorter periods of time; they may have been dependent on a critical intracellular concentration for that specific fatty acid (or metabolic derivative) which secondarily determined the reaction rates for esterification and secretion of the triglyceride. Accumulation of triglyceride in liver resulted from infusion of fatty acids containing 12 carbon atoms or more; more triglyceride seemed to accumulate when palmitic acid was infused than when other long chain fatty acids were infused. On examination of the triglyceride fatty acids of liver and perfusate by gas-liquid chromatography, it was determined that the triglyceride had been enriched with the infused fatty acid, although a definite relationship between the percentage of enrichment of the fatty acid in the triglyceride and the stimulation of output of triglyceride was not discernible. The rates of ketogenesis, normally of small magnitude in livers from fed animals, were similar in all groups except the one receiving palmitic acid, in which case the output of ketone bodies was less than that of the other groups. Stimulation of output of glucose by fatty acids may vary with the ability of the specific acid to be esterified and secreted or stored as triglyceride. Medium and short chain fatty acids exerted a larger and longer lasting effect on stimulation of output of glucose than did any of the long chain fatty acids; the effect of palmitic acid was minimal. The differential effects of the various free fatty acids on secretion of triglyceride by the liver may, in part, be the mechanism by which dietary factors in the intact animal influence the concentration of triglyceride in the serum.