Estrogen Receptor α Regulates Expression of the Orphan Receptor Small Heterodimer Partner

Abstract

Hormonal status can influence diverse metabolic pathways. Small heterodimer partner (SHP) is an orphan nuclear receptor that can modulate the activity of several transcription factors. Estrogens are here shown to directly induce expression of the SHP in the mouse and rat liver and in human HepG2 cells. SHP is rapidly induced within 2 h following treatment of mice with ethynylestradiol (EE) or the estrogen receptor ␣ (ER␣)-selective compound propyl pyrazole triol (PPT). SHP induction by these estrogens is completely absent in ER␣KO mice. Mutation of the human SHP promoter defined HNF-3, HNF-4, GATA, and AP-1 sites as important for basal activity, whereas EE induction required two distinct elements located between ؊309 and ؊267. One of these elements contains an estrogen response element half-site that bound purified ER␣, and ER␣ with a mutated DNA binding domain was unable to stimulate SHP promoter activity. This ER␣ binding site overlaps the known farnesoid X receptor (FXR) binding site in the SHP promoter, and the combination of EE plus FXR agonists did not produce an additive induction of SHP expression in mice. Surprisingly, induction of SHP by EE did not inhibit expression of the known SHP target genes cholesterol 7␣-hydroxylase (CYP7A1) or sterol 12␣-hydroxylase (CYP8B1). However, the direct regulation of SHP expression may provide a basis for some of the numerous biological effects of estrogens.Estrogens exert biological effects in numerous organs throughout the body. The role of estrogens in reproductive biology, the prevention of postmenopausal hot flushes, and the prevention of postmenopausal osteoporosis are well established (1). Estrogens reduce low density lipoprotein (LDL) 1 cholesterol levels and elevate HDL cholesterol levels (2-4), although these beneficial lipid changes may not translate into favorable clinical results (5). Estrogens may also inhibit the development of colon cancer (5), inhibit the development of Alzheimer's disease (6), and inhibit development of cataracts (7,8). The multitude of estrogen responses matches the widespread distribution of estrogen receptors (ERs) throughout numerous organs, with ER␣ expression the highest in uterus, pituitary, kidney, and adrenal gland and ER␤ expression highest in ovary, uterus, bladder, and lung (9). Although many of these actions of estrogens are due to the classic signaling pathway in which an ER binds to an estrogen response element in the promoter of a gene (10), it is now clear that many actions of estrogens are mediated by interaction of ER with other signaling pathways. For example, estrogens inhibit chronic and acute liver inflammation in the mouse by a mechanism that does not require ER activation of gene expression (11,12). This in vivo activity of ER correlates with the in vitro ability of ER to inhibit NFB signaling (13, 14), likely through a coactivator competition mechanism (15). Similarly, ER can regulate gene expression via interaction with AP-1 response elements (16).An additional mechanism by which ER could influence diverse s...

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Effects of a PPARG gene variant on obesity characteristics in Brazil

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The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

“…SHP activation by FXR ligands in hepatocytes leads to the repression of cholesterol 7␣-hydroxylase expression, the rate-limiting enzyme in the neutral pathway that leads to bile acid production from cholesterol (33). SHP is also a known target for other nuclear receptors, including the estrogen receptors and PPAR␥ (65,66), and is essential in the regulation of the expression/activity of hepatocyte NF4 and retinoid X receptor (66). A body of evidence suggest that SHP represents an important mediator of FXR activity and acts as a corepressor of FXR target genes in different physiological contexts (33,36,46,47).…”