Lipoprotein lipase modulates net secretory output of apolipoprotein B in vitro. A possible pathophysiologic explanation for familial combined hyperlipidemia.
We showed previously that net secretory output of apolipoprotein B (apo B) from cultured human hepatoma cells (HepG2) is regulated by rapid reuptake of nascent lipoproteins before they have diffused away from the vicinity of the cells. We now sought to determine if the nascent lipoproteins could be remodeled to enhance or impede reuptake. We found that lipoprotein lipase (LpL), an enzyme that hydrolyzes lipoprotein triglyceride, reduced HepG2 output of apo B to one-quarter to one-half of control. The reduction was apparent during co-incubations as short as 2 h and as long as 24 h. Heparin, which blocks receptor-mediated binding of lipoproteins, abolished the effect of LpL on apo B output, without causing enzyme inhibition. To assess uptake directly, we prepared labeled nascent lipoproteins. LpL tripled the cellular uptake of labeled nascent lipoproteins, from 15.2% +/- 0.7% to 48.7% +/- 0.3% of the total applied to the cells. Cellular uptake of 125I-labeled anti-LDL receptor IgG was unaffected by LpL; thus, LpL enhanced reuptake by altering lipoproteins, not receptors. Because LpL is present in the space of Disse in the liver, we conclude that LpL may act on newly secreted lipoproteins to enhance reuptake in vivo. LpL deficiency would reduce local reuptake of apo B, which would appear as overproduction, thereby providing a mechanistic link between partial LpL deficiency and familial combined hyperlipidemia.
Department of Physiology and Biochemistry, Medical College of Pennsylvania, Philadelphia 19129.
K J
KJ
Williams
K A
KA
Petrie
R W
RW
Brocia
T L
TL
Swenson
D001055:Apolipoproteins B / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D011973:Receptors, LDL / Q000032:analysis
D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D008071:Lipoprotein Lipase