New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation

Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, Massachusetts 02215, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 08/2009; 1791(11):1037-47. DOI: 10.1016/j.bbalip.2009.06.006
Source: PubMed


Epidemiological and clinical studies have found that at all ages women are twice as likely as men to form cholesterol gallstones, and this gender difference begins since puberty and continues through the childbearing years, which highlight the importance of female sex hormones. Estrogen is a crucial hormone in human physiology and regulates a multitude of biological processes. The actions of estrogen have traditionally been ascribed to two closely related classical nuclear hormone receptors, estrogen receptor 1 (ESR1) and ESR2. Recent studies have revealed that the increased risk for cholesterol gallstones in women vs. men is related to differences in how the liver metabolizes cholesterol in response to estrogen. A large number of human and animal studies have proposed that estrogen increases the risk of developing cholesterol gallstones by increasing the hepatic secretion of biliary cholesterol, which, in turn, leads to an increase in cholesterol saturation of bile. Furthermore, it has been identified that hepatic ESR1, but not ESR2, plays a major role in cholesterol gallstone formation in mice in response to high doses of 17beta-estradiol. The mechanisms mediating estrogen's action have become more complicated with the recent identification of a novel estrogen receptor, G protein-coupled receptor 30 (GPR30), a member of the seven-transmembrane G protein-coupled receptor superfamily. In this review, we provide an overview of the evidence for the lithogenic actions of estrogen through ESR1 and discuss the cellular and physiological actions of GPR30 in estrogen-dependent processes and the relationship between GPR30 and classical ESR1 on gallstone formation.

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Available from: Piero Portincasa
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    • "All these facts together highlight the effect of female gender on the pathogenesis of both types of GS. Oestrogen increases the biliary cholesterol secretion causing cholesterol supersaturation [23], while progesterone inhibits the GB contraction and function of sphincter of oddi causing bile stasis [24]. Therefore the effect of progesterone can be considered as the reason to have high incidence of both types of GS among females as pathogenesis of both cholesterol and black pigment GS is associated with gall bladder hypomotility [10]. "
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    ABSTRACT: Background Pathogenesis of gallstones (GS) is multifactorial and multiple genetic and environmental factors have been identified in different populations for different types of GS with varying prevalence. However the role of the each aetiological factor on the formation of mixed cholesterol and black pigment GS has not being addressed adequately. Hence in this study we attempted to compare known possible risk factors for mixed cholesterol and black pigment GS among two groups of patients with two types of GS. Methods The study was done on a cohort of patients with symptomatic GS admitted to the Teaching Hospital Peradeniya, Sri Lanka over a period of 18 months. Clinical and epidemiological data and physical parameters of the patients were recorded and surgically removed GS were analyzed chemically and physically to identify the type of GS. In addition lipid profile was done in all the patients with normal serum bilirubin levels. Results A total of 86 patients were included in the study. Mixed cholesterol GS was significantly common among females than males (χ2 test, p = 0.029). Mixed cholesterol GS was commonly seen among patients belonging to Moor ethnicity (χ2 test, p = 0.009). Majority of patients with mixed cholesterol GS had body mass index above 25 kg/m2 (χ2 test, p = 0.018). Black pigment GS were significantly common among patients with type II diabetes mellitus (Fisher’s exact test, p = 0.035). Further all the patients with chronic haemolytic anaemia and alcoholic cirrhosis had black pigment GS. Age, family history, Fasting Blood Glucose, dyslipidaemia, lipid profile, parity and use of oral contraceptive pills in females, smoking and alcohol intake in males did not differ significantly among patients in the two groups. Conclusion Gender, ethnicity and body mass index can be used to predict the formation of mixed cholesterol GS and black pigment GS.
    Full-text · Article · May 2014 · BMC Gastroenterology
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    • "For tricluster 1, we have identified NPC1L1, TMEM161B-AS1, POU5F1P3, POU5F1P4, POU5F1B, CCL2 as hub-genes that are coexpressed over all-time points. It has been observed in a previous study that high doses of estrogen augment intestinal cholesterol absorption attributable in part to an up-regulated expression of NPC1L1 which is known as intestinal sterol influx transporter [21]. CCL2 is found to play an important role in mediating cross-talk between cancer cells and stromal fibroblasts in breast cancer cells [22]. "
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    ABSTRACT: Background Estrogen is a chemical messenger that has an influence on many breast cancers as it helps cells to grow and divide. These cancers are often known as estrogen responsive cancers in which estrogen receptor occupies the surface of the cells. The successful treatment of breast cancers requires understanding gene expression, identifying of tumor markers, acquiring knowledge of cellular pathways, etc. In this paper we introduce our proposed triclustering algorithm δ-TRIMAX that aims to find genes that are coexpressed over subset of samples across a subset of time points. Here we introduce a novel mean-squared residue for such 3D dataset. Our proposed algorithm yields triclusters that have a mean-squared residue score below a threshold δ. Results We have applied our algorithm on one simulated dataset and one real-life dataset. The real-life dataset is a time-series dataset in estrogen induced breast cancer cell line. To establish the biological significance of genes belonging to resultant triclusters we have performed gene ontology, KEGG pathway and transcription factor binding site enrichment analysis. Additionally, we represent each resultant tricluster by computing its eigengene and verify whether its eigengene is also differentially expressed at early, middle and late estrogen responsive stages. We also identified hub-genes for each resultant triclusters and verified whether the hub-genes are found to be associated with breast cancer. Through our analysis CCL2, CD47, NFIB, BRD4, HPGD, CSNK1E, NPC1L1, PTEN, PTPN2 and ADAM9 are identified as hub-genes which are already known to be associated with breast cancer. The other genes that have also been identified as hub-genes might be associated with breast cancer or estrogen responsive elements. The TFBS enrichment analysis also reveals that transcription factor POU2F1 binds to the promoter region of ESR1 that encodes estrogen receptor α. Transcription factor E2F1 binds to the promoter regions of coexpressed genes MCM7, ANAPC1 and WEE1. Conclusions Thus our integrative approach provides insights into breast cancer prognosis.
    Full-text · Article · Mar 2013 · Algorithms for Molecular Biology
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    • "Cholesterol gallstone disease (CGD) is one of the most common digestive disease conditions in both industrialized and develop-ing western countries. Worldwide CGD prevalence ranges between 5% and 20% [1], being more common in women than men in every population that has been studied [2]. It is particularly prevalent in some specific ethnic groups including Mapuche and North American Indians as well as Chilean and Mexican Hispanics. "
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    ABSTRACT: Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.
    Full-text · Article · Jan 2012
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