Regulation of Low-Density Lipoprotein Receptor Activity by Estrogens and Phytoestrogens in a HepG2 Cell Model

Abstract

Background/Aims: Estrogen treatment is thought to lower low-density lipoprotein (LDL) cholesterol levels by increasing clearance through hepatic LDL receptors. This study aimed to determine the effect of estrogens and phytoestrogens on LDL receptor activity in a human hepatoma cell line, HepG2. Methods: HepG2 cells in culture were incubated for 24 h with estrogen or phytoestrogen and LDL receptor activity was measured by examining the cellular binding of colloidal gold-labelled LDL. Results: 17β-Estradiol significantly increased LDL receptor activity whereas estriol had negligible effects. Incubation with the isoflavonoids, formononetin, biochanin A and daidzein, caused significant elevations in receptor activity at concentrations above 40 µM. Coumestrol, a coumestan with a high level of estrogenic activity, caused a 3-fold increase in receptor activity at a concentration of 50 µM. Of the phytoestrogenic mammalian lignans enterolactone and enterodiol, only enterolactone displayed the ability to significantly upregulate LDL receptor activity at 50 µM. Conclusion: This study suggests that the LDL receptor-stimulating effect of natural estrogens is mainly due to estradiol and that the cholesterol-lowering effect of diets high in phytoestrogens may be due in part to their ability to increase hepatic LDL receptor activity.

The effect of estrogens and phytoestrogenic lignans on macrophage uptake of atherogenic lipoproteins

“…The two major phytoestrogenic lignans detected in human tissue are enterolactone and enterodiol, which are derived from plant lignans metabolised by colonic microflora. Enterodiol and enterolactone have been shown to display weak estrogenic and anti-estrogenic activity [45,46], as well as antioxidant activity [47], although we have found enterodiol to have a greater ability to inhibit LDL oxidation than enterolactone [48]. In the present study, these phytoestrogenic lignans had little influence upon LDL uptake into macrophages, but significantly reduced macrophage Lp(a) uptake, with enterodiol being the most effective.…”

The Effect of Fenugreek (Trigonella foenum-graecum) Seed and 17-β Estradiol on Serum Apelin, Glucose, Lipids, and Insulin in Ovariectomized Rats

“…Menopausal statement due to reduced estrogen secretion is associated with hyperlipidemia, which is defined by increased level of cholesterol, TG, LDL, and decreased level of HDL (17). It has been demonstrated that estrogen has a physiological role in lowering cholesterol through upregulation of hepatic LDL receptor, consequently leading to an enhanced clearance of blood cholesterol (18).…”

Isoflavone supplementation in postmenopausal women does not affect leukocyte LDL receptor and scavenger receptor CD36 expression: A double‐blind, randomized, placebo‐controlled trial

“…As IF in blood are associated with circulating lipoproteins, predominantly with LDL , they may be able to directly affect receptors involved in LDL‐uptake, in particular LDLR and CD36. In cell culture experiments, the IF genistein stimulated LDLR expression, and an increased LDLR activity was shown in the presence of the IF daidzein . Therefore, IF could have an impact on LDLR expression and activity as it has been shown for estradiol and by this mechanism may reduce serum LDL‐chol.…”