Cholesterol metabolism in human gallbladder mucosa: Relationship to cholesterol gallstone disease and effects of chenodeoxycholic acid and ursodeoxycholic acid treatment

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.

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Heterogeneity of Human Biliary Mucin: Functional Implications

Clinical Science ◽

10.1042/cs0860075 ◽

1994 ◽

Vol 86 (1) ◽

pp. 75-82 ◽

Cited By ~ 6

Author(s):

J. Henriëtte Klinkspoor ◽

Michel J. A. van Wijland ◽

Carolien A. M. Koeleman ◽

Willem van Dijk ◽

Guido N. J. Tytgat ◽

...

Keyword(s):

Cholesterol Gallstone ◽

Lectin Binding ◽

Gallstone Disease ◽

Functional Characterization ◽

The Other ◽

Binding Studies ◽

Human Gallbladder ◽

Patient Heterogeneity ◽

Model Bile

1. Human gallbladder mucin has been implicated as playing a role in the pathogenesis of gallstones. In previous studies no differences have been found in the content or composition of mucins derived from control bile or cholesterol gallstone bile. Until now, no differences were also found between these two groups of mucins with regard to their ability to cause cholesterol nucleation. In the accompanying paper we have reported that there is a strong heterogeneity of gallbladder mucins derived from individual patients (M. J. A. van Wijland, J. H. Klinkspoor, L. Th. de Wit, R. P. J. Oude Elferink, G. N. J. Tytgat and A. K. Groen, Clin Sci 1994; 86: 67–74). In the present study we further investigated a possible patient to patient heterogeneity of mucin by means of immunological and functional characterization of mucins isolated from hepatic bile of six different patients with gallstones. 2. Considerable heterogeneity was found. Two of the mucins barely reacted with a polyclonal anti-mucin antibody, whereas the other four mucins reacted very strongly. Lectin-binding studies indicated that the glycans of these two mucins expressed less D-N-acetylgalactosamine residues than the other four mucins. This was confirmed by analyses of the glycan compositions. These studies furthermore indicated that the glycans were of the O-linked type, contained α-D-N-acetylglucosamine and were fucosylated, sialy-lated and sulphated to different extents. Except for a strong heterogeneity in the sugar composition of the mucins, heterogeneity was also found in the biological activity of the mucins. The two immunologically diverging mucins nucleated cholesterol from model bile 1–2 days earlier and also caused an almost threefold more rapid rupture of cholesterol/phospholipid vesicles than the other mucins. 3. We conclude that considerable differences exist between mucins derived from individual patients and that the heterogeneity in glycan composition might play a role in the pathogenesis of gallstone disease.

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Ursodeoxycholic acid reduces lipid peroxidation and mucin secretagogue activity of human bile in cholesterol gallstone disease

Gastroenterology ◽

10.1016/s0016-5085(98)82230-0 ◽

1998 ◽

Vol 114 ◽

pp. A548-A549 ◽

Cited By ~ 1

Author(s):

Christoph von Ritter ◽

Nair Sreejayan ◽

Iris Müller ◽

Günther Meyer ◽

Dieter Jüngst

Keyword(s):

Lipid Peroxidation ◽

Ursodeoxycholic Acid ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Human Bile

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Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

Cholesterol ◽

10.1155/2013/298421 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

Agostino Di Ciaula ◽

David Q.-H. Wang ◽

Leonilde Bonfrate ◽

Piero Portincasa

Keyword(s):

Insulin Resistance ◽

Genetic Factors ◽

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Cholesterol Homeostasis ◽

Cholesterol Gallstones ◽

The Metabolic Syndrome ◽

Digestive Diseases

Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.

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