Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes

Azzaroli, Francesco; Mehal, Wajahat Z.; Soroka, Carol J.; Wang, Lin; Lee, John; Crispe, Nicholas; Boyer, James L.

doi:10.1053/jhep.2002.34511

Cited by 80 publications

(59 citation statements)

References 21 publications

(30 reference statements)

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“…46 The cytoprotective effects of UDCA and TUDCA have been attributed to the reduction of reactive oxygen species formation, 47 the prevention of mitochondrial dysfunction, 48 and the inhibition of apoptosis through both the intrinsic 49 and the extrinsic pathway. 50 These steroids can also activate specific nuclear receptors and G protein-coupled receptors influencing the expression of genes that encode proteins involved in the regulation of glucose, fatty acid, lipoprotein synthesis, energy metabolism, and the regulation of their own synthesis. 51 In vitro data There is in vitro evidence to support a chaperone activity for BAs.…”

Section: Lipids and Detergents (Bile Acids)mentioning

confidence: 99%

The therapeutic potential of chemical chaperones in protein folding diseases

Cortez¹,

Sim²

2014

Prion

211

155

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Section: Lipids and Detergents (Bile Acids)mentioning

confidence: 99%

The therapeutic potential of chemical chaperones in protein folding diseases

Cortez¹,

Sim²

2014

Prion

211

155

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“…Indeed, UDC modulates the apoptotic threshold, in part, by inhibiting the opening of the mitochondrial permeability transition pore and by preventing translocation of Bax both in vitro and in vivo. Recent data have also provided evidence that UDC enters the mitochondria, suggesting that its antiapoptotic effect may be a consequence of a modulation of mitochondrial perturbation [24].…”

Section: Introductionmentioning

confidence: 99%

Membrane structural changes support the involvement of mitochondria in the bile salt-induced apoptosis of rat hepatocytes

et al. 2002

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A B S T R A C TThe accumulation of toxic bile salts within the hepatocyte plays a key role in organ injury during liver disease. Deoxycholate (DC) and glycochenodeoxycholate (GCDC) induce apoptosis in vitro and in vivo, perhaps through direct perturbation of mitochondrial membrane structure and function. In contrast, ursodeoxycholate (UDC) and its taurine-conjugated form (TUDC) appear to be protective. We show here that hydrophobic bile salts induced apoptosis in cultured rat hepatocytes, without modulating the expression of pro-apoptotic Bax protein, and caused cytochrome c release in isolated mitochondria. Co-incubation with UDC and TUDC prevented cell death and efflux of mitochondrial factors. Using spin-labelling techniques and EPR spectroscopy analysis of isolated rat liver mitochondria, we found significant structural changes at the membrane-water surface in mitochondria exposed to hydrophobic bile salts, including modified lipid polarity and fluidity, altered protein order and increased oxidative injury. UDC, TUDC and cyclosporin A almost completely abrogated DC-and GCDC-induced membrane perturbations. We conclude that the toxicity of hydrophobic bile salts to hepatocytes is mediated by cytochrome c release, through a mechanism associated with marked direct effects on mitochondrial membrane lipid polarity and fluidity, protein order and redox status, without modulation of pro-apoptotic Bax expression. UDC and TUDC can directly suppress disruption of mitochondrial membrane structure, which may represent an important mechanism of hepatoprotection by these bile salts.

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“…This coordination between the extrinsic and intrinsic apoptotic pathways reinforces the critical role of the mitochondrial organelle during programmed cell death. In this regard, UDCA was shown to partially prevent the death receptor pathway of apoptosis in primary mouse hepatocytes co-cultured with fibroblasts that express the Fas ligand, possibly by its direct effects at the mitochondrial membrane (Azzaroli et al, 2002). …”

mentioning

confidence: 99%

Game and Players: Mitochondrial Apoptosis and the Therapeutic Potential of Ursodeoxycholic Acid

Solá

Aranha

Steer³

et al. 2007

Current Issues in Molecular Biology

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Apoptosis represents a universal and exquisitely efficient cellular suicide pathway essential for a variety of normal biological processes ranging from embryonic development to ageing. In fact, tissue homeostasis is dependent on the perfect balance between positive and negative signals that determines the decision between life and death. Therefore, any imbalance can result in a wide range of pathologic disorders associated with unwanted apoptosis or cell growth. During the apoptotic process, the molecular players interact closely with each other in ways relevant to accelerate or interrupt the cellular death process. In addition, two major pathways of apoptosis activation have been recognized as the "intrinsic" mitochondrial pathway and the "extrinsic" death receptor pathway. Although these pathways act independently to initiate apoptosis, a delicate balance and cross-talk between the extrinsic and intrinsic pathways is thought to occur in many cell types. Interestingly, we have shown that ursodeoxycholic acid (UDCA), an endogenous hydrophilic bile acid, is a potent inhibitor of apoptosis by either stabilizing the mitochondrial membrane or modulating the expression of specific upstream targets. Herein, we review the main effectors involved in the death machinery, describe how they interact to regulate apoptosis, and discuss the main pathways that control cell death and survival. Further, we address multiple interesting targets as well as the potential application of UDCA as a therapeutic modality for apoptosis-related disorders. IntroductionThe process of cell death typically follows one of two patterns: necrosis or apoptosis (Bayerdorffer et al., 1993). The first is the consequence of acute metabolic perturbation as it occurs in ischemia/reperfusion or acute drug-induced toxicity. In contrast, apoptosis represents the execution of a death program often initiated by specific stimuli. Nevertheless, it is important to note that, in certain occasions, rather than separate entities, apoptosis and necrosis are frequently the consequence of the same initiating factors and signaling pathways, representing extremes on a continuum of cell death (Bull et al., 1983;Hofmann, 2002).Apoptosis is an active mechanism by which metazoan organisms quickly eliminate cells in response 124 Solá et al.The molecular mechanisms of programmed cell death are highly conserved throughout evolution. Studies in Caenorhabditis elegans (C. elegans) have demonstrated that cell demise is carried out by specific cellular pathways (Hall et al., 1997), suggesting that it may be more "programmed" than initially thought. In fact, cell death in C. elegans is regulated only by three genes: ced-3, ced-4 and ced-9 (Fig. 1). Further, Egl-1 blocks the activity of Ced-9, an inhibitor of Ced-4 that complexes with and activates the cysteinic protease Ced-3 (Conradt and Horvitz, 1998).The apoptosis process can be subdivided into initiation, effector and degradation phases (Kroemer et al., 1995). In mammalian cells, the initiation stage depends on the ty...

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Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes

Cited by 80 publications

References 21 publications

The therapeutic potential of chemical chaperones in protein folding diseases

The therapeutic potential of chemical chaperones in protein folding diseases

Membrane structural changes support the involvement of mitochondria in the bile salt-induced apoptosis of rat hepatocytes

Game and Players: Mitochondrial Apoptosis and the Therapeutic Potential of Ursodeoxycholic Acid

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