HEPATIC-UPTAKE OF BETA-VLDL IN CHOLESTEROL-FED RABBITS

The hepatic uptake of intravenously injected beta-very low density lip oprotein (beta-VLDL) in rabbits fed 2% (w/w) cholesterol for 3 weeks w as investigated. In vitro studies were also conducted to examine the s pecificity and the capacity of the uptake in isolated liver parenchyma l cells. The hepatic uptake of beta-VLDL was 15.8 +/- 6.7% (n = 6) in the cholesterol-fed rabbits as compared to 26.6 +/- 7.5% (n = 6) of th e injected dose in control rabbits (P < 0.05). Although this is a frac tional reduction, it represents a more than 10-fold increase in absolu te hepatic uptake of lipoproteins in the cholesterol-fed rabbits. In t hese animals the liver parenchymal, endothelial, and Kupffer cells too k up 10.2 +/- 2.7%, 3.0 +/- 0.9%, and 1.8 +/- 0.4% of the injected dos e, respectively, compared to 25.9 +/- 6.1%, 3.6 +/- 1.6%, and 1.5 +/- 0.8% of the injected dose in chow-fed controls. However, taking into a ccount the high plasma lipoprotein levels in the cholesterol-fed rabbi ts, the absolute cellular uptake was 10-fold increased in the parenchy mal liver cells and more than 20-fold increased in the nonparenchymal cells. In vitro results indicated a 40% down-regulation of the specifi c receptor for beta-VLDL in the parenchymal cells, and this, together with an increased competition for binding sites in the hypercholestero lemic rabbits, probably explains the reduced uptake of beta-VLDL in te rms of % of injected dose observed in vivo. In vitro data suggested th at the receptor involved in both hypercholesterolemic and normolipemic rabbits was the apolipoprotein (apo) B,E receptor. On a per cell basi s, parenchymal cells from chow-fed control animals took up 2.4 +/- 0.8 % of the injected dose per 10(9) cells; this uptake was reduced to 1.1 +/- 0.5% in hypercholesterolemic animals. No differences in uptake of beta-VLDL in nonparenchymal liver cells were observed on a per cell b asis between the two feeding groups, indicating that binding sites inv olved in this uptake are not down-regulated by cholesterol feeding. On the contrary, the absolute uptake in the nonparenchymal liver cells i s greatly increased in hypercholesterolemic rabbits as compared to con trols. In cholesterol-fed rabbits the three different liver cell types took up approximately the same amount of beta-VLDL per cell. The live r non-parenchymal cells, therefore, assume a prominent role in uptake of beta-VLDL in hypercholesterolemic rabbits, accounting for more than 30% of the total hepatic uptake as compared to 16% in control animals . Electron microscopic studies showed a significant accumulation of li pids in all cell types investigated from cholesterol-fed rabbits, whil e no such lipid accretion could be observed in control rabbits. The in vivo data show that the nonparenchymal cells, notably the Kupffer cel ls, play an important role in catabolizing beta-VLDL in hypercholester olemic rabbits.