CONCENTRATION-DEPENDENT EFFECTS OF EICOSAPENTAENOIC ACID ON VERY-LOW-DENSITY LIPOPROTEIN SECRETION BY THE ISOLATED-PERFUSED RAT-LIVER

The effects of increasing concentrations of eicosapentaenoic acid (20: 5n-3; EPA) and oleic acid (18:1n-9; OA) on esterification to triacylgl ycerols (TG) and phospholipids (PL), and the relationship to formation and secretion of the very low density lipoproteins (VLDL) were compar ed in the isolated perfused rat liver. Mixtures of EPA and OA were als o studied to determine whether substrate levels of one fatty acid migh t influence the metabolism of the other. The basal perfusion medium, w hich contained 30% (vol/vol) washed bovine erythrocytes, 6% (wt/vol) b ovine serum albumin (BSA), and 100 mg glucose/dL in Krebs-Henseleit bi carbonate buffer (pH 7.4) was recycled through the liver for 2 h. EPA or OA, as a complex with 6% BSA, was infused at rates of 70, 105, 140 and 210 mumol/h. In other experiments, mixtures of EPA and oleic acid (70 mumol total), with molar percentages of 100, 75, 50, 25 and 0% of each fatty acid were infused per hour. BSA (6%) in the buffer was infu sed alone and served as the control. At an infusion rate of 70 mumol E PA per hour, hepatic VLDL lipid output was not different from that whe n fatty acid was not infused (approximately half that when 70 mumol OA /h was infused). However, when larger amounts of EPA and OA were infus ed individually, rates of VLDL secretion were stimulated to a similar extent with either fatty acid. The apparent inhibitory influence of EP A on TG synthesis and VLDL lipid output when 70 mumol EPA were infused per hour could also be overcome by the presence of as little as 25 mo l% OA in a mixture. Furthermore, the presence of EPA in the infused fa tty acid mixture stimulated the incorporation of OA into TG, enhancing VLDL secretion. When EPA or OA was infused at rates exceeding 70 mumo l/h, a constant amount of endogenously-derived fatty acids was incorpo rated into VLDL-TG, similar in amount to that when exogenous fatty aci d was not supplied. However, when EPA was infused at a rate of 70 mumo l/h, incorporation of endogenous fatty acids was depressed. At this lo w rate of EPA infusion, esterification of EPA and endogenous fatty aci d was inhibited. Conceivably, this may reflect the existence of indepe ndently-regulated pools of fatty acid (exogenous and endogenous), in t hat only exogenously available fatty acid preferentially enrich the se creted TG. Enrichment of PL by the infused fatty acid at the higher ra tes of fatty acid infusion showed similar, but much less pronounced, d ifferences between VLDL and liver, compared to that for TG, providing additional evidence for a distinct metabolic pool of PL used for VLDL fabrication. It now appears that when EPA is available to the liver in high enough concentrations, or when OA (or other fatty acids?) is pre sent in substrate amounts along with EPA, competing reactions and/or s pecific inhibitory influences of EPA on enzymatic reactions are overco me, and EPA can be utilized in a manner similar to OA for esterificati on to TG with subsequent enhanced VLDL formation and secretion.