Mechanism of the hypertriglyceridemia induced by tumor necrosis factor administration to rats

Abstract

4 h after intravenous injection of recombinant HuTNF-α to fed rats, an increase in heart, diaphragm, and plasma lipoprotein lipase activity was observed. At the same time, a 40–60% decrease in enzymic activity in epididymal fat pad and kidney and 40% decrease in hepatic lipase activity in liver had occurred. Similar results were obtained 20 h after injection of recombinant HuTNF-α into fasted rats. Pretreatment with Indomethacin did not affect the changes in tissue lipoprotein lipase activity observed following recombinant HuTNF-α administration. Serum triacylglycerol concentration increased by 2- and 6-fold; 4 and 20 h after recombinant HuTNF-α administration. Disappearance of 14C-labeled triacylglycerol from the circulation after injection of small chylomicrons, biosynthetically labeled in their triacylglycerol and cholesterol moieties, was lower in TNF-treated than in control rats. However, the clearance rate of triacylglycerol was the same or even higher in recombinant HuTNF-α treated rats (assuming that 14C-labeled chylomicron triacylglycerol represents the serum triacylglycerol pool). The livers of recombinant HuTNF-α-treated rats and controls contained similar amounts of 14C-labeled lipids, but less [ 3H]cholesterol, suggesting that in recombinant HuTNF-α-treated rats, the liver took up chylomicron remnant particles enriched with triacylglycerol. Separation of the d < 1.04 g/ml fraction of serum obtained from control and recombinant HuTNF-α treated rats by zonal ultracentrifugation revealed that in recombinant HuTNF-α-treated rats the lipoprotein particles were less lipolyzed than in controls. The secretion rate of [ 3H]triacylglycerol into the serum was determined 90 min after injection of [ 3H]palmitate albumin complex and Triton WR 1339. In recombinant HuTNF-α-treated rats, the secretion of [ 3H]triacylglycerol into plasma was 48% higher than in controls. It is suggested that the increase in lipoprotein lipase activity of heart and diaphragm resulted from an indirect effect of TNF. It is concluded that the increase in serum triacylglycerol in the recombinant HuTNF-α-treated rats is due mainly to an increased secretion of triacylglycerol by the liver. Impaired lipolysis, probably due to a fall in hepatic lipase could also contribute to the rise in plasma triacylglycerol.