LIPOPROTEIN-LIPASE ENHANCES REMOVAL OF CHYLOMICRONS AND CHYLOMICRON REMNANTS BY THE PERFUSED-RAT-LIVER

Lipoprotein lipase has been found to efficiently mediate binding of li poproteins to cell surfaces and to the low density lipoprotein (LDL) r eceptor-related protein (LRP) under cell culture conditions (Beisiegel et al. 1991. Proc. Natl. Acad. Sci USA. 88: 8242-8346). This supports the previously proposed idea that the lipase could have a role in rec eptor-mediated uptake of chylomicron remnants in the liver. We have in vestigated the effects of lipoprotein lipase on the clearance of chylo microns during perfusions of rat livers. The chylomicrons were doubly labeled in vivo with [C-14]retinol (in retinyl esters) and with [H-3]o leic acid (in triacylglycerols) and were collected from lymph. In the absence of any lipase the clearance of chylomicron label from the perf usion medium was slow. Addition of lipoprotein lipase caused lipolysis of chylomicron triacylglycerols as evidenced by increased levels of C -14-labeled fatty acids in the perfusate. Simultaneously, the level of [C-14]retinyl esters in the perfusate decreased dramatically, indicat ing core-particle removal. Similar effects were seen with an unrelated lipase from Pseudomonas fluorescens. To discriminate between the effe cts of lipolysis and a true liganding effect of the lipoprotein lipase protein, the active site inhibitors tetrahydrolipstatin(R) and hexade cylsulfonylfluoride were used to reduce or totally inhibit the catalyt ical activity. With lipase covalently inhibited by the latter inhibito r lipolysis during perfusions was low or absent. Nonetheless, the inhi bited enzyme had a clear effect on the removal of chylomicrons by the liver. With 1.2 mu g of inhibited lipase/ml perfusate, about 70% of th e core label had been removed after 15 min as compared to about 20% in perfusions without lipase. With identical amounts of active lipoprote in lipase protein, more than 90% of the label was removed. We conclude that any lipase causing lipolysis of chylomicrons can stimulate their clearance by the liver, but that lipoprotein lipase has an additional effect on the removal, which is not dependent on its catalytic activi ty.