Overexpression of estrogen receptor α increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice

Abstract

We explored whether there is an ''estrogen-ERa-SREBP-2'' (for estrogen-estrogen receptor subtype a-sterolregulatory element binding protein-2) pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17b-estradial (E 2 ) at 6 mg/day or E 2 plus the antiestrogenic agent ICI 182,780 at 125 mg/day and on chow or fed a high-cholesterol (1%) diet for 14 days. To monitor changes in cholesterol biosynthesis and newly synthesized cholesterol secreted into bile, incorporation into digitonin-precipitable sterols in mice treated with 25 mCi of [ 3 H]water was measured in extracts of liver and extrahepatic organs 1 h later and in hepatic biles 6 h later. ERa upregulated SREBP-2, with resulting activation of SREBP-2-responsive genes in the cholesterol biosynthetic pathway. The E 2 -treated mice continued to synthesize cholesterol in spite of its excess availability from high dietary cholesterol, which reflects a loss in controlling the negative feedback regulation of cholesterol synthesis. These alterations augmented biliary cholesterol secretion and enhanced the lithogenicity of bile. However, these lithogenic effects of E 2 were fully blocked by ICI 182,780. We conclude that during estrogen treatment, more newly synthesized cholesterol determined by the estrogen-ERa-SREBP-2 pathway is secreted into bile, leading to biliary cholesterol hypersecretion. These studies provide insights into therapeutic approaches to cholesterol gallstones in high-risk subjects, especially those exposed to high levels of estrogen.-Wang, H. H., N. H. Afdhal, and D. Q-H. Wang. Overexpression of estrogen receptor a increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice. J. Lipid Res. 2006. 47: 778-786.

Role of Estrogens in the Regulation of Liver Lipid Metabolism

“…In mice, natural variation in estrogen cycling is associated with changes in expression of bile acid synthesis gene expression (Della Torre et al 2016). Additionally, estrogen enhances synthesis of bile acids, which is also preventable with concurrent treatment with an ERα antagonist (Wang et al 2006). Furthermore, E2 fails to promote bile secretion in mice lacking ERα (Wang et al 2004), suggesting that estrogen acts through ERα to promote bile secretion.…”

The diversity of sex steroid action: regulation of metabolism by estrogen signaling

“…Also, estrogen significantly enhances the activity of HMG-CoA reductase, the ratelimiting enzyme in hepatic cholesterol biosynthesis, under high dietary cholesterol loads, suggesting that there could be an increased delivery of cholesterol to bile from de novo synthesis in the liver (Everson et al 1991, Wang et al 2006a. Studies report that estrogen could increase the capacity of dietary cholesterol to induce cholesterol supersaturation of bile and high doses of estrogen augment intestinal cholesterol absorption leading to the overproduction of bile and the formation of cholesterol gallstones (Henriksson et al 1989, Uhler et al 1998.…”

Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

“…At molecular levels, the "estrogen-ERα-SREBP-2" pathway can cause biliary cholesterol hypersecretion . Also, estrogen can stimulate the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis (Reichen et al, 1987;Wang et al, 2006). Additionally, estrogen can enhance intestinal cholesterol absorption (Duan et al, 2006).…”