EBHU18, a novel derivative of fatty acid bile acid conjugates, prevents cholesterol gallstone formation in experimental mice

FABACs (fatty acid–bile acid conjugates) are synthetic molecules that are designed to treat a range of lipid disorders. The compounds prevent cholesterol gallstone formation and diet-induced fatty liver, and increase reverse cholesterol transport in rodents. The aim of the present study was to investigate the effect of FABACs on cholesterol efflux in human cells. Aramchol (3β-arachidylamido-7α,12α,5β-cholan-24-oic acid) increased cholesterol efflux from human skin fibroblasts in a dose-dependent manner in the absence of known efflux mediators such as apoA-I (apolipoprotein A-I), but had little effect on phospholipid efflux. An LXR (liver X receptor) agonist strongly increased Aramchol-induced cholesterol efflux; however, in ABCA1 (ATP-binding cassette transporter A1)-deficient cells from Tangier disease patients, the Aramchol effect was absent, indicating that activity of ABCA1 was required. Aramchol did not affect ABCA1 expression, but plasma membrane levels of the transporter increased 2-fold. Aramchol is the first small molecule that induces ABCA1-dependent cholesterol efflux without affecting transcriptional control. These findings may explain the beneficial effect of the compound on atherosclerosis.

Download Full-text

Studies on the Pathogenesis of Cholesterol Gallstone Formation: Alterations of Bile Acid Transport and Liver Surface Membrane Lipid Structure by Estrogens

Gallstones ◽

10.1007/978-1-4615-7064-6_15 ◽

1979 ◽

pp. 251-265 ◽

Cited By ~ 2

Author(s):

Francis R. Simon ◽

Manuel Gonzalez ◽

Roger Davis

Keyword(s):

Bile Acid ◽

Cholesterol Gallstone ◽

Surface Membrane ◽

Gallstone Formation ◽

Membrane Lipid ◽

Acid Transport ◽

Bile Acid Transport ◽

Lipid Structure ◽

Liver Surface

Download Full-text

Peroxisome Proliferator-Activated Receptor-γ Prevents Cholesterol Gallstone Formation in C57bl Mice by Regulating Bile Acid Synthesis and Enterohepatic Circulation

BioMed Research International ◽

10.1155/2018/7475626 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12

Author(s):

Gang Wang ◽

Tao Han ◽

ShiJia Wang ◽

Min Chen ◽

Yueming Sun ◽

...

Keyword(s):

Bile Acid ◽

Enterohepatic Circulation ◽

Cholesterol Gallstone ◽

Gallstone Formation ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Expression Of Genes

To investigate the role of the peroxisome proliferator-activated receptor-γ (PPARγ) in the progression of cholesterol gallstone disease (CGD), C57bl/6J mice were randomized to the following groups (n=7/group): L (lithogenic diet, LGD), LM (LGD+pioglitazone), CM (chow diet+pioglitazone), and NC (normal control, chow diet). Gallbladder stones were observed by microscopy. Histological gallbladder changes were assessed. Bile acids (BA) and cholesterol were measured in the serum, bile, and feces. Proteins and mRNA expression of genes involved in BA metabolism and enterohepatic circulation were assessed by western blotting and real-time RT-PCR. PPARγ activation was performed in LO2 cell by lentivirus transfection and in Caco2 cell by PPARγ agonist treatment. Downregulation of farnesoid X receptor (FXR) by small interference RNA (siRNA) was performed in L02 cells and Caco2 cells, respectively. Results showed that pharmacological activation of PPARγ by pioglitazone prevents cholesterol gallstone formation by increasing biliary BA synthesis and enterohepatic circulation. Activated PPARγ induced the expression of genes involved in enterohepatic circulation and bile acid synthesis (like PCG1α, BSEP, MRP2, MRP3, MRP4, NTCP, CYP7A1, CYP27A1, ASBT, OSTα, and OSTβ). Downregulation of FXR repressed expression of partial genes involved in BA enterohepatic circulation. These findings suggest a new function of PPARγ in preventing CGD by handling BA synthesis and transport through a FXR dependent or independent pathway.

Download Full-text

Effect of different varieties of pectin and guar gum on plasma, hepatic and biliary lipids and cholesterol gallstone formation in hamsters fed on high-cholesterol diets

British Journal Of Nutrition ◽

10.1079/bjn19980077 ◽

1998 ◽

Vol 79 (5) ◽

pp. 463-471 ◽

Cited By ~ 17

Author(s):

Elke A. Trautwein ◽

Angelika Kunath-Rau ◽

Helmut F. Erbersdobler

Keyword(s):

Bile Acid ◽

Guar Gum ◽

Plasma Lipids ◽

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Plasma Cholesterol ◽

Gallstone Formation ◽

Hamster Model ◽

Biliary Lipids ◽

Faecal Weight

The effect of high- (hePE) and low- (lePE) esterification pectin and high- (hvGG) and low-(lvGG) viscosity guar gum on plasma, hepatic and biliary lipids and on prevention of cholesterol gallstones was investigated in male golden Syrian hamsters (Mesocricetus auratus). Hamsters were fed on cholesterol-rich (4g/kg), gallstone-inducing diets for 6 weeks. The diets were supplemented with 80g hePE, lePE, hvGG or lvGG/kg or 80g additional cellulose/kg. No significant differences in plasma total cholesterol and triacylglycerol concentrations between hvGG and lvGG and the gallstone-inducing or cellulose-enriched diets were observed. The hePE diet produced a 16% (non-significant) reduction in total plasma cholesterol but significantly decreased the plasma triacylglycerol level by 45%. The lePE diet caused only minor changes in plasma lipids. Hepatic cholesterol concentrations were significantly higher in hamsters fed on hvGG, lvGG, hePE or lePE primarily due to the accumulation of esterified cholesterol. Supersaturated bile samples, with lithogenic indices ranging from 1.6 to 2.0, were determined with all diets. The hePE and lePE diets slightly altered the bile acid profile by increasing glycocholic acid and decreasing taurochenodeoxycholic acid concentrations resulting in a higher cholic: chenodeoxycholic acid ratio. Cholesterol gallstone formation was not substantially inhibited by the two varieties of pectin and guar gum. The hvGG, lvGG, hePE and lePE diets did not alter faecal weight and caused only minor increases in faecal bile acid excretion. In general, the present findings demonstrate that dietary pectins and guar gums had only minor effects on cholesterol metabolism and did not prevent cholesterol gallstone formation in this hamster model. Possible explanations for this lack of a distinct response to pectin and guar gum are discussed.

Download Full-text

Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion

Nature Communications ◽

10.1038/s41467-021-27758-8 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Hai Hu ◽

Wentao Shao ◽

Qian Liu ◽

Ning Liu ◽

Qihan Wang ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Common Disease ◽

Intestinal Cholesterol Absorption ◽

Fecal Transplantation ◽

Hepatic Expression

AbstractCholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

Download Full-text

Increased risk of cholesterol gallstone formation in subjects with apolipoprotein E4 genotype

European Journal of Gastroenterology & Hepatology ◽

10.1097/00042737-199812000-00047 ◽

1998 ◽

Vol 10 (12) ◽

pp. A8

Author(s):

K. J. van Erpecum ◽

P. Portincasa ◽

E. R.M. Eckhardt ◽

B. J.M. van de Heijning ◽

A. K. Groen ◽

...

Keyword(s):

Cholesterol Gallstone ◽

Gallstone Formation ◽

Apolipoprotein E4 ◽

Increased Risk

Download Full-text

Biliary lipid composition and gallstone formation in rabbits fed on soy protein, cholesterol, casein and modified casein

Biochemical Journal ◽

10.1042/bj2630293 ◽

1989 ◽

Vol 263 (1) ◽

pp. 293-296 ◽

Cited By ~ 9

Author(s):

T Ozben

Keyword(s):

Bile Acid ◽

Soy Protein ◽

Acid Level ◽

Gallstone Formation ◽

Biliary Lipid ◽

Lipid Levels ◽

Bile Acid Concentration ◽

Bile Acid Level ◽

Lithogenic Index ◽

Biliary Lipid Composition

In four experimental groups, rabbits were fed on diets containing soy beans, soy beans plus cholesterol (1%, w/w), casein and modified casein for 8 weeks. Biliary lipid levels, lithogenic-index values and the rate of gallstone formation were determined. The highest mean relative concentrations (mol%) of cholesterol and phospholipid were found in the soy bean + cholesterol group, and the highest mean relative bile acid concentration was in the soy bean group. The lowest mean relative cholesterol and phospholipid values were found in the soy bean and modified casein groups respectively. The lowest mean relative bile acid level was in the soy bean + cholesterol group. The highest lithogenic index and rate of gallstone formation were in the soy bean + cholesterol group, and the lowest values were in the soy bean group. The modification of casein used was effective in decreasing the lithogenic effect of casein on gallstone formation.

Download Full-text