Estrogen-stimulated transcytosis of desialylated ligands and α2 macroglobulin in rat liver

Abstract

Previous studies have shown that treatment of rats with 17 α-ethynylestradiol (EE) causes the appearance in bile of intravenously injected, desialylated ligands, including asialofetuin and low density lipoprotein (LDL). Here we show that activated α 2-macroglobulin ( α 2-M *), but not insulin, transferrin or acetylated LDL, shows the same phenomenon. α 2-M * appearance in bile in EE-treated rats was inhibited by receptor associated protein, but not unlabelled asialofetuin, strongly implicating the α 2-macroglobulin receptor ( α 2MR/LRP) receptor in this process. Asialofetuin, apolipoprotein B (ApoB) of LDL and α 2-M * appeared undegraded in the bile of EE-treated but not control rats. When LDL was injected, not only was intact apolipoprotein B detected in bile, but the profile of cholesterol esters appearing in bile was characteristic of the injected human LDL rather than rat lipoproteins. After floatation of the bile on KBr gradients, intact Apo B and cholesterol esters characteristic of human LDL were found at the normal density of LDL suggesting that the majority of the lipoprotein particle remains intact. Stimulation of transcytosis was specific to estrogens, and was highest with 17 α-ethynylestradiol. After subcutaneous injection of 0.05 mg/kg body weight of ethynylestradiol, sufficient to give a measurable increase in transcytosis, the plasma concentration of ethynylestradiol rose to 2.2 nM. Thus estrogen-stimulated transcytosis of desialylated ligands and α 2-M * would be expected at physiological estrogen concentrations.