Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts

Heuman, Douglas M.; Mills, A. Scott; McCall, Janice B.; Hylemon, Philip B.; Pandak, William M.; Vlahčevič, Z. Reno

doi:10.1016/0016-5085(91)90602-h

Cited by 219 publications

(113 citation statements)

References 36 publications

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“…Several studies have suggested that the taurine conjugates may have more pronounced hepatoprotective effects than UDCA. 28,29,47 Studies with glycine-conjugated UDCA, however, indicate a similar hepatoprotective effect for taurine and glycine conjugates of UDCA. 48 The little differences in conjugation between the average and high doses of UDCA make it unlikely that this factor is of relevance when patients with PSC are treated with high doses of UDCA.…”

Section: Discussionmentioning

confidence: 97%

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

et al. 2004

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Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (؎20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high-dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10 -13 mg/kg/d (n ‫؍‬ 18) biliary UDCA represented 43.1% ؉ 0.3% (mean ؉ SD) of total bile acids; at a UDCA dose of 14 -17 mg/kg (n ‫؍‬ 14), its biliary content increased to 46.9% ؉ 0.3%, at 18 -21 mg/kg (n ‫؍‬ 34) to 55.9% ؉ 0.2%, at 22-25 mg/kg (n ‫؍‬ 12) to 58.6% ؉ 2.3%, and at 26 -32 mg/kg (n ‫؍‬ 8) to 57.7% ؉ 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22-25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22-25 mg/kg may be more effective than lower doses. (HEPATOLOGY 2004;40:693-698.)

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Section: Discussionmentioning

confidence: 97%

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

et al. 2004

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“…21,22 For example, coadministration of UDCA to rats fed toxic bile acids inhibited apoptosis and prevented liver injury. 23 In vitro studies showed that UDCA prevented apoptosis induced by deoxycholic acid, ethanol, transforming growth factor ␤, Fas ligand, and okadaic acid by decreasing mitochondrial depolarization with subsequent inhibition of cytochrome C release and caspase activation. 24,25 However, although some studies suggested an effect of bile acids on calcium homeostasis, [26][27][28][29] there are no data regarding the role of UDCA during ER stress-induced apoptosis.…”

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confidence: 99%

“…Our data show that TG-induced apoptosis results primarily from activation of caspase-12, as a result of elevation of cytosolic calcium. It seems that in this model of ER stressinduced apoptosis, mitochondria play a secondary role and tauroursodeoxycholic acid (TUDCA), which represents the most hydrophilic conjugate of UDCA, 23 protects cells by blocking a calcium-mediated apoptotic pathway with inhibition of caspase-12 activation.…”

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confidence: 99%

Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress–induced caspase-12 activation

et al. 2002

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Activation of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of caspase-12 activation and its effect on calcium homeostasis in an ER stress-induced model of apoptosis. The human liver-derived cell line, Huh7, was treated with thapsigargin (TG) to induce ER stress. Typical morphologic changes of ER stress preceded development of apoptotic changes, including DNA fragmentation and cleavage of poly (adenosine diphosphateribose) polymerase (PARP), as well as activation of caspase-3 and -7. Elevation of intracellular calcium levels without loss of mitochondrial membrane potential (MMP) was shown using Fluo-3/Fura-red labeling and flow cytometry, and confirmed by induction of Bip/GRP78, a calcium-dependent chaperon of ER lumen. These changes were accompanied by procaspase-12 processing. TUDCA abolished TG-induced markers of ER stress; reduced calcium efflux, induction of Bip/GRP78, and caspase-12 activation; and subsequently inhibited activation of effector caspases and apoptosis. In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation. This novel mechanism of TUDCA action suggests new intervention methods for ER stress-induced liver disease. (HEPATOLOGY 2002;36:592-601.)

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“…3 Accumulation of toxic bile acids results in hepatocellular damage, ultimately leading to liver fibrosis and cirrhosis. Bile acid cytotoxicity has been demonstrated on hepatocytes in vitro 4,5 and in vivo in rat models, 6,7 and they are known to induce hepatocyte apoptosis. 8 There is generally a correlation between bile acid hydrophobicity and cytotoxicity: the hydrophobic lithocholic and deoxycholic acids exert the most toxic effects, whereas the hydrophilic ursodeoxycholic and cholic acids have little toxicity.…”

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Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

Clouzeau-Girard

Guyot

Combe

et al. 2006

Laboratory Investigation

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During cholestasis, bile acids accumulate in the liver, and induce cellular alterations. Cholestasis is a major cause of liver fibrosis. We have used precision-cut liver slices (PCLS) in culture to investigate the effects of bile acids on hepatic cells. Rat PCLS were placed on an insert in a vial containing culture medium, and gently agitated on a roller platform. PCLS were treated with 100 lM taurolithocholate (TLC), taurodeoxycholate (TDC) or taurocholate (TC) for 24 or 48 h. PCLS viability was measured, and immunohistochemistry was performed with antibodies against active caspase 3, platelet-derived growth factor (PDGF) receptor-b and ED-A fibronectin. TDC and TLC, two hydrophobic bile acids, induced hepatocyte necrosis and apoptosis, whereas TC, an hydrophilic bile acid, improved slice viability as compared with controls. Both TDC and TC induced biliary epithelial cell proliferation, together with portal fibroblast proliferation and activation, as shown by PDGF receptor-b and ED-A fibronectin expression. TLC induced biliary epithelial cell apoptosis. Our results indicate that individual bile acids induce cell type-specific effects in a complex liver microenvironment. The fact that PCLS support biliary epithelial cell and portal fibroblast proliferation will make this model very useful for the study of the mechanisms involved in portal fibrosis.

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Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts

Cited by 219 publications

References 36 publications

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress–induced caspase-12 activation

Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices

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