Mechanism of poloxamer 407-induced hypertriglyceridemia in the rat

One 300 mg i.p. injection of the nonionic surfactant poloxamer 407 (Pluronic F-127) produces a significant increase above control of both circulating cholesterol and triglyceride (TG) concentrations. The present study was conducted to determine the effect of poloxamer 407 (P-407) on the capacity to hydrolyze circulating TG by lipoprotein lipase (LPL) in an attempt to determine the mechanism of action of P-407. The concentration of TG in the rat following a single 300 mg i.p. injection of P-407 was marked, increasing from 84 +/- 10 to 3175 +/- 322 mg/dL at 24 hr. The maximal rate of TG accumulation (5.74 mg/dL/min) in the plasma of P-407-injected rats occurred between 2 and 4 hr post-injection. In vitro incubation of LPL with P-407 significantly inhibited enzyme activity with an inhibitory concentration at which 50% of the enzymatic activity was lost of approximately 24 microM. Concentrations of P-407 exceeding 350 microM in vitro completely inhibited LPL activity. The effects of P-407 on the enzymatic activity of LPL in post-heparin plasma obtained following a single 300 mg dose of P-407 to rats demonstrated greater than 95% suppression of LPL activity 3 hr post-injection compared with controls. Inhibition of LPL activity was greater than 90% as long as 24 hr following a single i.p. injection of P-407. However, while the heparin-releasable fraction of capillary-bound LPL was inhibited in the plasma, LPL activity significantly increased in cardiac and skeletal muscle in poloxamer-injected animals compared with sham-injected controls. Although there was no significant change in LPL activity in adipose tissue, testes, and lung resulting from P-407 treatment, LPL activity increased by 37% in myocardium, 69% in soleus, and 66% in gastrocnemius muscle in P-407-injected rats when compared with controls. Our studies would suggest that the predominant mechanism by which P-407 induced an increase in circulating TG was by a reduction in the rate at which TG was hydrolyzed due to inhibition of heparin-releasable LPL by the surfactant.