Cholelithiasis induced in the Syrian hamster: Evidence for an intramucinous nucleating process and down regulation of cholesterol 7α-hydroxylase (CYP7) gene by medroxyprogesterone

Abstract

This report reviews previously published studies from our laboratory and shows some recent morphological data obtained with scanning and transmission electron microscopy regarding gallstone formation and alteration of the gallbladder epithelium in the Syrian hamster model. Both male and female hamsters were treated with female sex steroids (estradiol alone, estradiol and medroxyprogesterone, medroxyprogesterone alone) during one month. The results show that the Syrian hamster is a good model to study bile changes, gallbladder structure changes, including gallstone formation, and the regulation of cholesterol metabolism at the molecular level. Arguments in favor of this animal model are presented and, during gallstone formation, epithelial cell changes, anionic mucus secretion, and formation of gallbladder luminal deposits can be demonstrated. Recent molecular biology observations related to the effect of female sex steroids on liver cholesterol 7α‐hydroxylase (CYP7) gene suggest that progestin alone or primed by estrogen down regulates CYP7 transcription and activity. In addition, progesterone in cell culture systems has been shown to enhance intracellular accumulation of free cholesterol by increasing its uptake and synthesis and by decreasing its esterification by inhibiting the activity of acylcoenzyme A: cholesterol acyltransferase. Non‐esterified cholesterol is free to migrate to the extracellular spaces and may contribute to nucleation within the bile. It is suggested that these effects of progesterone on cholesterol metabolism combined with the CYP7 gene down regulation, physical changes in the mucus and the hypomotility of the gallbladder and biliary ducts result in hypersaturation of cholesterol in the bile which favors gallstone formation. Microsc. Res. Tech. 39:56–70, 1997. © 1997 Wiley‐Liss, Inc.

Artichoke Extract Lowered Plasma Cholesterol and Increased Fecal Bile Acids in Golden Syrian Hamsters

“…For example, flavonoids, such as luteolin, quercetin and apigenin (3–5 µ m ) augmented progesterone signaling by inhibiting 20 alpha‐hydroxysteroid dehydrogenase in mice (Shimada et al , ). Progesterone enhanced intracellular accumulation of free cholesterol by increasing its uptake and synthesis while down‐regulating CYP7 transcription, thus decreasing bile acid synthesis in hamsters (Cabeza and Miranda, ; Gilloteaux et al , ). The mechanisms of sex differences in effects of ALE to increase fecal bile acids and neutral sterols need further study.…”

Intracellular Liposomes and Cholesterol Deposits in Chronic Cholecystitis and Biliary Sludge

“…Estrogens enhance hepatic cholesterol secretion [57] and, along with progestins, reduce bile acid secretion [58^61]. In the Syrian hamster model, progestins were to be strong hormones and metabolites were to be the most likely causes for bile saturation [27^29] through a specific repression of the liver 7a-hydroxylase gene [41,62]. This enzyme is key for the cholesterol esterification [63^64] and it is also repressed during lactation in offsprings and mothers, while the gene is significantly reexpressed after weaning in both mothers and offspring [41,62].…”

“…In the Syrian hamster model, progestins were to be strong hormones and metabolites were to be the most likely causes for bile saturation [27^29] through a specific repression of the liver 7a-hydroxylase gene [41,62]. This enzyme is key for the cholesterol esterification [63^64] and it is also repressed during lactation in offsprings and mothers, while the gene is significantly reexpressed after weaning in both mothers and offspring [41,62]. The changes in the mucus components make it more viscous [56] and may include apical cell sloughings [65].…”

“…All of these sequential or overlapping events could very well be entwined with other factors of gallstone nucleation, causing cholelithiasis where mucus is also rendered with lipids a soap-like by-product [41]. This soapy mixture could then precipitate with cholesterol and, in association with liposomes, further grows by accretion to make a gallstone nucleus packet in association with liposomes and cholesterol.…”

The Gallbladder of the Electric Ray Torpedo Marmorata Risso Displays Excrescent Cholecystocytes with Merocrine and Apocrine‐Like Secretions

“…This study was undertaken to study the morphologic peculiarities of the Torpedo marmorata gallbladder, also a predator but an Elasmobranch. It is noted that the gallbladder secretory activity resembles the complex morphologic changes observed in cases of human cholecystitis and cholelithiasis (Gilloteaux et al, 1997a, b, 2003, 2004) and in the Syrian hamster gallbladder following treatment with sex steroids (Gilloteaux et al, 1992, 1993a, b).…”