Binding and degradation of lipoprotein(a) and LDL by primary cultures of human hepatocytes. Comparison with cultured human monocyte-macrophages and fibroblasts.
Although lipoprotein(a) (Lp[a]) has structural similarities to low-density lipoprotein (LDL) that include the presence of apolipoprotein B100, there is some disagreement over the strength of its interaction with the LDL receptor and its cellular catabolism by the LDL receptor-mediated pathway. To clarify this subject we evaluated LDL receptor-mediated binding and degradation of Lp(a) and LDL in three human cell lines. The binding of 50 nmol/L Lp(a) at 37 degrees C to the LDL receptor of primary hepatocytes, macrophages, and fibroblasts was only 10%, 29%, and 29% of the respective value obtained with 50 nmol/L LDL. Analysis of 4 degrees C binding curves indicated that Lp(a) and LDL had equal affinities for the LDL receptor of fibroblasts, whereas maximal binding of Lp(a) was remarkably lower than that of LDL. LDL receptor-mediated degradation of 50 nmol/L Lp(a) in hepatocytes, macrophages, and fibroblasts was only 17%, 22%, and 26%, respectively, of the value obtained with 50 nmol/L LDL and varied greatly among the cells in that it was lowest in hepatocytes, an order of magnitude greater in macrophages, and two orders of magnitude greater in fibroblasts. In contrast, the nonspecific degradation rate of Lp(a) was similar to that of LDL in each of the three tested cell lines. However, the proportion of the degradation of Lp(a) that was nonspecific varied greatly, being 76%, 58%, and 33% in hepatocytes, macrophages, and fibroblasts, respectively. These studies indicate that not only is Lp(a) recognized by the LDL receptor but also that, in fibroblasts, Lp(a) and LDL have equal affinities for the LDL receptor, although Lp(a) has a much lower receptor occupancy than LDL. Additionally, they show that there are great cellular differences in the LDL receptor-mediated degradation of Lp(a). If these results can be extrapolated in vivo, where normal LDL levels are 40- to 50-fold higher than those of Lp(a), it would be unlikely that the hepatic LDL receptor is significantly involved in the degradation of Lp(a).
Snyder
M L
ML
Department of Medicine, Pritzker School of Medicine, University of Chicago, IL 60637.
Hay
R V
RV
Whitington
P F
PF
Scanu
A M
AM
Fless
G M
GM
D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism
D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D011973:Receptors, LDL