Evaluation of a radioiodinated triglyceride for assessing alterations in hepatic lipid metabolism.

Abstract

A triglyceride, glycerol-2-palmitoyl-1,3-di-15-(p-iodophenyl) pentadecanoate (DPPG), was synthesized and radiolabelled for evaluation as a potential functional liver scintigraphic agent. DPPG was compared to naturally-occurring triglycerides, triolein (TO) and tripalmitin (TP) as substrates for hepatic lipase (HL) and liver acid lipase. Enzymatic hydrolysis of DPPG was similar to TP, with both demonstrating about nine-fold less hydrolysis than TO in the assay for acid lipase. The susceptibility of TO, TP and DPPG to hydrolysis by HL was comparable. The biodistribution of the three triglycerides following intravenous administration showed similar levels of accumulation of radioactivity in the liver. Moreover, DPPG readily associated with HDL upon administration and when incubated with rat plasma, suggesting that the liver uptake is due to lipoprotein-mediated processes. Comparison of the liver uptake of DPPG in normal, diabetic, tumor-bearing and heparin pretreated female rats revealed a decrease in uptake and clearance of radioactivity that was correlated with HL and acid lipase activities of these groups. Comparison of males and females showed that females had significantly higher levels of HL and acid lipase activities, and showed a greater accumulation of radioactivity in the liver following administration of either DPPG or TP. Male rats fed an alcohol containing diet for six weeks resulted in an accumulation of triglyceride in the liver, a decrease in HL activity, and a decrease in liver uptake of DPPG when compared with controls. Female rats fed ethanol had more erratic plasma and liver lipid levels suggesting variability in the development in alcoholic fatty liver. HL and acid lipase levels were also depressed in female alcoholic rats coincident with a depressed liver uptake of DPPG when compared to controls. To enhance the liver uptake, DPPG was incorporated into several different types of emulsions. Administration of these preparations to rats demonstrated a significant enhancement in liver uptake of radioactivity. However, in these studies it became clear that the particle size of the emulsion was a critical factor in minimizing nonspecific phagocytosis. Therefore, based on these results, DPPG shows potential as a probe to study liver lipid metabolism.