Increased binding of low density lipoprotein to liver membranes from rats treated with 17α-ethinyl estradiol

Pharmacologic doses of 17α-ethinyl estradiol have been reported to cause a marked lowering of plasma lipoprotein levels in the rat. The drop in plasma low density lipoprotein (LDL) is associated with enhanced uptake of LDL by the liver. In the current studies, we show that membranes prepared from livers of ethinyl estradiol-treated rats exhibit a 3- to 10-fold increase in saturable binding sites for human ¹²⁵I-LDL. These binding sites resembled the LDL receptors previously described in extrahepatic human, mouse, and bovine cells in that they: 1) showed a marked preference for human LDL as opposed to human high density lipoprotein (HDL); 2) required calcium; 3) failed to bind LDL in which the lysine residues had been acetylated or methylated in vitro; and 4) were destroyed by pronase. Hepatic uptake of intravenously administered human ¹²⁵I-HDL was 12-fold higher in estradiol-treated rats as compared with controls. Uptake of ¹²⁵I-LDL was competitively inhibited by unlabeled human LDL, but not by human HDL. Moreover, methylated human ¹²⁵I-HDL, which did not bind to the LDL site on membranes, was taken up by the liver in vivo at a 10-fold lower rate than ¹²⁵I-LDL. These data suggest that the ¹²⁵I-LDL membrane binding site that was detected in vitro mediated the uptake of ¹²⁵I-LDL in vivo. Livers of untreated and ethinyl estradiol-treated rats also exhibited a saturable binding site for human ¹²⁵I-HDL. This site bound human HDL much more avidly than human LDL. HDL binding was not increased by ethinyl estradiol treatment, did not require calcium, and was not destroyed by pronase. Whether the ¹²⁵I-LDL and ¹²⁵I-HDL binding sites function as hepatic lipoprotein receptors in untreated rats is not yet known.