Glycosaminoglycans and chylomicron metabolism in control and nephrotic rats

Nephrotic patients and rats with experimentally induced nephrotic syndrome have elevated plasma triglycerides and impaired triglyceride removal. This may be due to a defective interaction of chylomicrons and very low density lipoproteins with lipoprotein lipase. Since the glycosaminoglycan, heparan sulfate, was found to stimulate the lipoprotein lipase reaction in vitro, we investigated the plasma heparan sulfate content and measured the urinary excretion of heparan sulfate in control rats and rats with experimentally induced nephrotic syndrome. In addition, we studied the effect of heparan sulfate on the rate of removal of radiolabeled chylomicrons in nephrotic rats. Glycosaminoglycan concentrations in plasma were the same in control and nephrotic rats, although 35S incorporation in high charge glycosaminoglycans was markedly reduced. In addition, in nephrotic rats there is a marked reduction in the urinary excretion of heparan sulfate and chondroitin sulfate suggesting a markedly reduced turnover of these glycosaminoglycans. This was associated with increased plasma triglycerides in nephrotic rats. Nephrotic rats showed a reduced rate of clearance of injected chylomicrons. Intravenous administration of heparan sulfate completely and immediately corrected the chylomicron removal defect. We also noted a log-dose response effect of administered heparan sulfate on chylomicron removal. This effect was not due to a release of soluble lipoprotein lipase by heparan sulfate. These findings suggest that a rapidly turning over fraction of plasma heparan sulfate may play an important role in chylomicron clearance.