Interaction of beta-very-low-density lipoproteins with rat liver cells.

Cholesteryl-ester-rich very-low-density lipoproteins (beta-VLDL) are considered to be atherogenic because in vitro they can provoke cholesterol accumulation in macrophages. The greatest population of macrophages resides inside the liver and in the present study the rat beta-VLDL uptake by the various rat liver cell types is determined in vivo and compared to the uptake of rat VLDL. beta-VLDL isolated from cholesterol-fed rats was iodinated and injected into the rat. After 10 min of circulation, 45% of the injected beta-VLDL was found in the liver. A low-temperature cell-isolation procedure shows that rat liver parenchymal cells form the major site for beta-VLDL uptake (96%) and, consequently, rat liver macrophages (nonparenchymal liver cells) do not perform a quantitatively significant role in the uptake of these lipoproteins. In vitro competition studies indicate that apolipoprotein (apo) E is the site recognised by liver parenchymal cells and even a 600-fold excess of apo-E-free human LDL was an ineffective competitor. Furthermore it can be demonstrated that induction of apo-B,E receptors on liver parenchymal cells by estrogen treatment does not result in a significant increased uptake of beta-VLDL. These data show that recognition of beta-VLDL is presumably exerted by the remnant receptor. Intracellular processing of both the apolipoproteins and phospholipids of beta-VLDL was followed by subcellular distribution studies. It appears that, within 45 min, 75% of the apolipoproteins are degraded and subsequently released from the liver. In contrast the phospholipids remain associated with the liver for a prolonged time and a specific transfer to the mitochondrial fraction is found. It can be concluded that liver parenchymal cells form in vivo the major site for beta-VLDL uptake and it appears that recognition of beta-VLDL is coupled to internalization and processing of both the apolipoproteins and phospholipids by a route which involves the lysosomes.