Depletion of lipoprotein lipase after heparin administration.

Abstract

Some or most of the turnover of lipoprotein lipase (LPL) occurs by dissociation from vascular endothelial sites in extrahepatic tissues and further degradation in the liver. Heparin greatly enhances this dissociation and delays but does not abolish uptake in the liver, raising the possibility that heparin could lead to accelerated catabolism of functional LPL. To investigate this, we determined time curves for heparin (anti-factor Xa activity) and for LPL and hepatic lipase after injection in rats of two doses of conventional unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The high dose (250 U/kg) of both heparins resulted in similar initial levels of LPL activity in plasma, but at 30 minutes the activity with LMWH had declined by more than 80%, whereas with UFH it remained essentially unchanged during this time. In contrast, time curves for heparin activity in blood were similar for the two heparins. The low dose (50 U/kg) led to lower initial levels of LPL activity with LMWH in spite of slower elimination of heparin activity from the blood. These results agree with previous studies that indicate that LMWH has a similar ability as UFH to release LPL, but a lesser ability to delay its removal by the liver. Only slight differences were noted in the time curves for hepatic lipase with the two heparins. To assess the possible depletion of the Upases, we administered a second large dose of conventional heparin. One hour after the first injection, the second injection resulted in lower plasma LPL activities in all four groups. This depletion of releasable LPL was more pronounced with high-dose LMWH (49% of that in saline-treated controls versus about 60% in the other groups). The LPL activity released by the second injection remained significantly depressed with low-dose LMWH and the high dose of either heparin at 4 hours, but had returned to normal after 24 hours. By contrast, no depletion of hepatic lipase activity could be shown at any time. The results showed that release of LPL into the circulating blood is followed by a period during which time the stores of functional LPL are depleted. This occurs with both UFH and LMWH; the difference between the two heparins lies more in the kinetics of the LPL removal process than in its ultimate result {Arterioscler Thromb. 1993;13:1391-1396 KEY WORDS • low-molecular-weight heparin heparin clearance • in vivo • rats• hepatic lipase • endothelium • lipase clearance H eparin has been used clinically for about 50 years, and its efficacy in the prophylaxis and treatment of thrombosis is well documented. In addition to its anticoagulant activity, heparin greatly increases the activity of two Upases in plasma: lipoprotein lipase (LPL) of extrahepatic origin, which hydrolyzes mainly triglycerides in chylomicra and very-lowdensity lipoproteins, and hepatic lipase (HL), which acts preferentially on remnants from chylomicra and very-low-density lipoproteins and on high-density lipoproteins. 1 The "lipolytic effect" of heparin comes from its ability to displace t...

Biphasic effects of low-molecular-weight and conventional heparins on chylomicron clearance in rats.

“…6 In the present study, however, the experimenter did not know which rat received which preparation. The code was broken only after all experiments and analyses had been completed.…”

“…In these rats LPL activity in plasma remained elevated at 1 hour. 6 Hence, they represented an intermediate situation compared with the 5-minute groups, in which both heparin and LPL values were high in the blood, or the 1-hour groups given the low doses of heparin, in which heparin had disappeared virtually completely, and LPL values had returned to control levels.…”

“…We have recently 6 found that both types of heparin cause a transient reduction of available LPL activity. This depletion seems to correlate with the retarded chylomicron clearance observed here.…”

“…In the accompanying article 6 we present evidence that release of LPL into the blood by heparin leads to accelerated uptake and catabolism of the enzyme in the liver 7 and a temporary depletion of functional LPL. This raised the question of what effect LPL depletion might have on the metabolism of triglyceride-rich lipoproteins.…”

“…6 Chylomicrons (10 mg triglyceride/kg body wt) were injected in an exposed jugular vein 5 minutes, 1 hour, 4 hours, or 24 hours after the heparins or saline (controls). Ten minutes before injection of the chylomicrons, the animals had been anesthetized.…”