Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile

Hussaini, S. Hyder; Pereira, Stephen P.; Murphy, Gérard M.; Dowling, R. H.

doi:10.1002/hep.1840220619

Cited by 50 publications

(39 citation statements)

References 48 publications

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“…Early studies by Low-Beer and Nutter (135) reported that treating control individuals with metronidazole, an antibiotic effective against anaerobic bacteria, significantly decreased the cholesterol saturation index of bile. Moreover, excess DCA in bile has been reported to decrease the nucleation time for cholesterol crystallization (136,137). In total, these results suggest a possible link between intestinal bacteria, DCA, and the risk of cholesterol gallstone disease in some patients.…”

Section: Secondary Bile Acids and Diseasementioning

confidence: 78%

Bile salt biotransformations by human intestinal bacteria

Ridlon

Kang

Hylemon

2006

Journal of Lipid Research

2,329

2,417

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Secondary bile acids, produced solely by intestinal bacteria, can accumulate to high levels in the enterohepatic circulation of some individuals and may contribute to the pathogenesis of colon cancer, gallstones, and other gastrointestinal (GI) diseases. Bile salt hydrolysis and hydroxy group dehydrogenation reactions are carried out by a broad spectrum of intestinal anaerobic bacteria, whereas bile acid 7-dehydroxylation appears restricted to a limited number of intestinal anaerobes representing a small fraction of the total colonic flora. Microbial enzymes modifying bile salts differ between species with respect to pH optima, enzyme kinetics, substrate specificity, cellular location, and possibly physiological function. Crystallization, site-directed mutagenesis, and comparisons of protein secondary structure have provided insight into the mechanisms of several bile acid-biotransforming enzymatic reactions. Molecular cloning of genes encoding bile salt-modifying enzymes has facilitated the understanding of the genetic organization of these pathways and is a means of developing probes for the detection of bile salt-modifying bacteria. The potential exists for altering the bile acid pool by targeting key enzymes in the 7a/b-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.-Ridlon, J. M., D-J. Kang, and P. B. Hylemon. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 2006. 47: 241-259.

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Section: Secondary Bile Acids and Diseasementioning

confidence: 78%

Bile salt biotransformations by human intestinal bacteria

Ridlon

Kang

Hylemon

2006

Journal of Lipid Research

2,329

2,417

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“…Similarly, low serum levels of apo A have been linked to decreased cholesterol crystallization in the bile, 33 and low serum levels of HDL have been associated with increased biliary cholesterol saturation and bile acid hyposecretion, 8,[30][31][32] which reduces cholesterol solubility in the bile and leads to gallstone formation. 34 Although the exact role of low levels of total cholesterol and/or LDL in gallstone formation is unclear, a number of indirect observations suggest a possible inverse association between total cholesterol and gallstone pathogenesis. A higher prevalence of gallstones has been suggested among men on cholesterol-lowering diets and among subjects who experienced rapid weight loss, a behavior often correlated with lower cholesterol levels.…”

Section: Discussionmentioning

confidence: 99%

Serum lipid levels and the risk of biliary tract cancers and biliary stones: A population‐based study in China

Andreotti

Chen

Gao

et al. 2007

Intl Journal of Cancer

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Biliary tract cancers, encompassing the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a populationbased case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (≥160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI 5 1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI 5 1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI 5 2.8-8.1), compared to the reference group (third quintile: 90-124 mg/dl). Participants in the lowest quintile of high-density lipoprotein (HDL) (<30 mg/dl) had a 4.2-fold risk of biliary stones (95% CI 5 3.0-6.0), an 11.6-fold risk of gallbladder cancer (95% CI 5 7.3-18.5), and a 16.8-fold risk of bile duct cancer (95% CI 5 9.1-30.9), relative to the reference group (third quintile: 40-49 mg/dl). In addition, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A (apo A) were inversely associated with biliary stones; whereas low levels as well as high levels of total cholesterol, LDL, apo A and apolipoprotein B (apo B) were associated with excess risks of biliary tract cancers. Our findings support a role for serum lipids in gallstone development and biliary carcinogenesis. ' 2007 Wiley-Liss, Inc.Key words: serum lipid levels; gallstones; biliary tract cancer Biliary tract cancers, consisting of tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. 1,2 Gallstones are the most important known risk factor for all three biliary tract cancer subsites. Specifically, cholesterol gallstones (composed mainly of cholesterol) and mixed gallstones (composed of both cholesterol and bilirubin) are most strongly associated with gallbladder cancer. 2,3 Furthermore, cholesterol gallstones and gallbladder cancer share a number of putative risk factors, including obesity, high fat diet and hyperlipidemia. 2,4 Hyperlipidemia is generally characterized by high serum levels of total cholesterol, triglycerides, low-density-lipoprotein (LDL), and low levels of high-density-lipoprotein (HDL). High triglycerides and low HDL have been most consistently associated with gallstones, whereas the associations of total cholesterol and LDL with gallstones are less consistent. [5][6][7] Cholesterol gallstone pathogenesis involves cholesterol saturation of the bile duct due to the hypersecretion of cholesterol from the liver 8 ; however, the exact role of individual lipids, lipoproteins and apolipoproteins is less clear.Given the relationship between hyperlipidemia and gallsto...

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“…Abcb11 transgenic mice display a characteristic lithogenic phenotype including rapidly recycling of bile salts, a more hydrophobic bile salt pool, and enrichment with TDC, the secondary bile salt metabolized from cholate by the colonic flora (41,42). Cholesterol gallstone patients have been reported to display higher biliary TDC concentrations compared with stone-free controls (43), and increased TDC levels promote cholesterol crystallization in model and human biles in vitro (13,44). Also of note, a recent genome-wide analysis in inbred mice identified higher hepatic gene expression of both FXR and SHP in mice carrying gallstone susceptibility alleles at these loci (45), as was observed in our transgenic mice.…”

Section: Abcb11 Overexpression Alters Hepatic Lipid Metabolismmentioning

confidence: 99%

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Figge

Lammert

Paigen

et al. 2004

Journal of Biological Chemistry

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Abcb11 encodes for the liver bile salt export pump, which is rate-limiting for hepatobiliary bile salt secretion. We employed transthyretin-Abcb11 and BACAbcb11 transgenes to develop mice overexpressing the bile salt export pump in the liver. The mice manifest increases in bile flow and biliary secretion of bile salts, phosphatidylcholine, and cholesterol. Hepatic gene expression of cholesterol 7␣-hydroxylase and ileal expression of the apical sodium bile salt transporter are markedly reduced, whereas gene expression of targets of the nuclear bile salt receptor FXR (ileal lipid-binding protein, short heterodimer partner (SHP) is increased. Because these changes in gene expression are associated with an increased overall hydrophobicity of the bile salt pool and a 4-fold increase of the FXR ligand taurodeoxycholate, they reflect bile salt-mediated regulation of FXR and SHP target genes. Despite the increased biliary secretion of bile salts, fecal bile salt excretion is unchanged, suggestive of an enhanced enterohepatic cycling of bile salts. Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls. We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression. Because these mice are resistant to hepatic lipid accumulation, regulation of Abcb11 may be important for the pathogenesis and treatment of steatohepatitis.

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Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile

Cited by 50 publications

References 48 publications

Bile salt biotransformations by human intestinal bacteria

Bile salt biotransformations by human intestinal bacteria

Serum lipid levels and the risk of biliary tract cancers and biliary stones: A population‐based study in China

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

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