Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes

Benz, Christine; Angermüller, Sabine; Töx, Ulrich; Klöters-Plachky, Petra; Riedel, H; Sauer, Peter; Stremmel, Wolfgang; Stiehl, A.

doi:10.1016/s0168-8278(98)80208-0

Cited by 131 publications

(93 citation statements)

References 16 publications

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“…Both bile acids mitigate mitochondrial insufficiency and toxicity by inhibiting Bax translocation from cytosol to mitochondria (18,20). Membrane stability inhibits cytochrome c release, thereby reducing downstream events such as caspase activation and substrate cleavage (43). In addition, TUDCA can inhibit endoplasmic reticulum stress-induced cell death by blocking a calciummediated apoptotic pathway (44).…”

Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats

Rodrigues

Solá

Nan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

184

128

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Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, modulates cell death by interrupting classic pathways of apoptosis. Intracerebral hemorrhage (ICH) is a devastating acute neurological disorder, without effective treatment, in which a significant loss of neuronal cells is thought to occur by apoptosis. In this study, we evaluated whether TUDCA can reduce brain injury and improve neurological function after ICH in rats. Administration of TUDCA before or up to 6 h after stereotaxic collagenase injection into the striatum reduced lesion volumes at 2 days by as much as 50%. Apoptosis was Ϸ50% decreased in the area immediately surrounding the hematoma and was associated with a similar inhibition of caspase activity. These changes were also associated with improved neurobehavioral deficits as assessed by rotational asymmetry, limb placement, and stepping ability. Furthermore, TUDCA treatment modulated expression of certain Bcl-2 family members, as well as NF-B activity. In addition to its protective action at the mitochondrial membrane, TUDCA also activated the Akt-1͞protein kinase B␣ survival pathway and induced Bad phosphorylation at Ser-136. In conclusion, reduction of brain injury underlies the wide-range neuroprotective effects of TUDCA after ICH. Thus, given its clinical safety, TUDCA may provide a potentially useful treatment in patients with hemorrhagic stroke and perhaps other acute brain injuries associated with cell death by apoptosis.

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Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats

Rodrigues

Solá

Nan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

184

128

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“…1 Antiapoptotic effects of UDCA have been shown in vitro and in vivo in the rat. 37,38 They were associated with a reduction of the MMPT and of mitochondrial cytochrome c release. 1,38 A recent study showed that UDCA, via activation of the epidermal growth factor receptor and MAPK, induces a survival signal in hepatocytes that may contribute to the antiapoptotic effect.…”

Section: Protection Against Bile Acid-induced Apoptosismentioning

confidence: 99%

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Paumgartner¹

2002

Hepatology

649

387

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“…19,20 One of the proposed mechanisms by which UDCA improves liver function during cholestasis or other liver injury relates to the antiapoptotic effects of UDCA. 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.…”

mentioning

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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Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes

Cited by 131 publications

References 16 publications

Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats

Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

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

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