Tauroursodeoxycholic Acid Prevents Bax-Induced Membrane Perturbation and Cytochrome<i>c</i>Release in Isolated Mitochondria

Rodrigues, Cecília M. P.; Solá, Susana; Sharpe, Juanita C.; Moura, José J. G.; Steer, Clifford J.

doi:10.1021/bi026979d

Cited by 107 publications

(80 citation statements)

References 62 publications

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“…This suggestion is also consistent with the independent observation that transient expression of the phosphorylated form of eIF2␣ induced a preconditioned, stress-resistant state that rendered cells less susceptible to other stress-induced signals (34). It is also worth noting that TUDCA has been shown to stabilize mitochondrial membranes and thereby to reduce apoptosis in isolated rat hepatocytes (35). Whether such a membrane-stabilizing effect occurs within enterocyte mitochondria following parenteral TUDCA administration is unknown.…”

Section: Discussionsupporting

confidence: 83%

Conditional Intestinal Lipotoxicity in Apobec-1-/- Mttp-IKO Mice

Luo

Kennedy

Davidson

2007

Journal of Biological Chemistry

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Mammalian small intestinal lipid absorption requires the coordinated interactions of apolipoprotein B (apoB) and the microsomal triglyceride transfer protein (Mttp). The observation that apoB100 displays greater dependence on Mttp availability than does apoB48 prompted us to examine the phenotype of Mttp deletion in an Apobec-1 ؊/؊ background (i.e. apoB100 Mttp-IKO). 20% apoB100 Mttp-IKO mice died on a chow diet, and >90% died following high fat feeding (versus 0 and 11% apoB48 Mttp-IKO mice, respectively). Intestinal adaptation occurred in apoB48 Mttp-IKO mice in response to high fat feeding, evidenced by increased bromodeoxyuridine incorporation and villus lengthening, changes that did not occur in apoB100 Mttp-IKO mice. There was an exaggerated unfolded protein response (UPR), which became more pronounced in apoB100 Mttp-IKO mice. To examine the role of endoplasmic reticulum stress and the UPR in the lipotoxic effects of Mttp deletion, we administered tauroursodeoxycholate to apoB100 Mttp-IKO mice upon initiation of high fat feeding. Tauroursodeoxycholate administration abrogated the UPR but produced an unexpected acceleration in the onset of lethality in apoB100 Mttp-IKO mice. The findings demonstrate that there is activation of the UPR with lethal lipotoxicity in conditional intestinal apoB100 Mttp-IKO mice. Together the data provide the first plausible biological evidence for a survival advantage for mammalian intestinal apoB mRNA editing. Lipid absorption and the secretion of triglyceride (TG)2 -rich lipoproteins (chylomicrons) from enterocytes of the mammalian small intestine are critically dependent on the coordinated interactions of two dominant genes. These include the structural protein apolipoprotein B (apoB) and the resident endoplasmic reticulum (ER) protein microsomal triglyceride transfer protein (Mttp) (1). Proper lipidation of apoB is achieved through the lipid transfer functions of Mttp, and this step is essential to maintaining the conformational integrity of the nascent apoB protein as it enters the luminal ER and initiates nascent lipoprotein biogenesis (1). Limiting lipid availability or defective expression and/or function of Mttp leads predictably to a failure of lipidation of the nascent apoB polypeptide, which in turn causes its misfolding and presecretory degradation (reviewed in Ref.2). The physiological relevance of this pathway is illustrated by the phenotype associated with abetalipoproteinemia where mutations in the MTTP gene are associated with failure of lipid export from both enterocytes and hepatocytes and serum levels of apoB are extremely low or undetectable (3).The requirements for Mttp-mediated lipidation of the apoB protein exhibit an important pattern of isoform dependence. Studies in hepatoma cells and in primary murine hepatocytes using pharmacological inhibitors of Mttp have demonstrated that apoB100 is dramatically more susceptible to presecretory degradation with limiting Mttp than is the shorter isoform, apoB48 (4, 5). These findings were reproduced in mice with ...

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Section: Discussionsupporting

confidence: 83%

Conditional Intestinal Lipotoxicity in Apobec-1-/- Mttp-IKO Mice

Luo

Kennedy

Davidson

2007

Journal of Biological Chemistry

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“…The involvement of a5b1 integrin and PI3K/AKT signaling was ruled out because TUDCA-mediated protection from TNF-induced caspase-3 activation is insensitive toward blocking PI3K by wortmannin or the a5b1 integrinblocking hexapeptide GRGDSP. In addition, TUDCA acts on the permeability of the mitochondrial membrane and the concomitant release of cytochrome c. 33 In HT29 cells, similar protection from TNF-induced cytochrome c release from the mitochondria (data not shown), as well as caspase-9 activation, was observed. Finally, TUDCA could also interfere in cell membrane composition or structure and inhibit crosslinking of transmembrane TNF receptors.…”

Section: Tudca Prevents Intestinal Epithelial Cell Death D Laukens Et Almentioning

confidence: 75%

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Laukens

Devisscher

Bossche

et al. 2014

Laboratory Investigation

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Ulcerative colitis (UC) is characterized by increased epithelial cell death and subsequent breakdown of the intestinal epithelial barrier, which perpetuates chronic intestinal inflammation. Since fecal bile acid dysmetabolism is associated with UC and tauroursodeoxycholic acid (TUDCA) has been shown to improve murine colitis, we evaluated the effect of TUDCA on intestinal epithelial cell death in a mouse model of UC-like barrier dysfunction elicited by dextran sulfate sodium (DSS). We identified the prevention of colonic caspase-3 induction, a key proapoptotic marker which was also over-activated in UC, as the earliest event resulting in a clear clinical benefit. Whereas vehicle-treated mice showed a cumulative mortality of 40%, all TUDCA-treated mice survived the DSS experiment during a 14-day follow-up period. In line with a barrier protective effect, TUDCA decreased bacterial translocation to the spleen and stimulated mucin production. Similarly, TUDCA inhibited lipopolysaccharide-induced intestinal permeability and associated enterocyte apoptosis. The anti-apoptotic effect was confirmed in vitro by a dose-dependent inhibition of both receptor-dependent (using tumor necrosis factor and Fas ligand) and receptor-independent (staurosporine) caspase-3 induction in HT29 colonic epithelial cells. These data imply that caspase-3 activation is an early marker of colitis that is prevented by TUDCA treatment. These data, together with the previously reported beneficial effect in colitis, suggest that TUDCA could be an add-on strategy to current immunosuppressive treatment of UC patients.

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“…Steer's 33 group recently reported that UDCA can prevent insertion of recombinant Bax into isolated rat liver mitochondria, thereby providing a mechanism for protection from apoptosis by UDCA. In studies to be reported elsewhere, we could not duplicate this effect with L1210 cells and recombinant Bax, unless the Bax was first 'activated', 34 that is, by exposure to octyl glucoside.…”

Section: Discussionmentioning

confidence: 99%

A mechanism for the proapoptotic activity of ursodeoxycholic acid: effects on Bcl-2 conformation

2004

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Ursodeoxycholic acid (UDCA), a relatively nontoxic bile acid, enhanced the apoptotic response of tumor cells to both photosensitizers that cause photodamage to Bcl-2 and to the nonpeptidic Bcl-2/Bcl-x L antagonist HA14-1. The latter agent binds to the surface pocket formed by the BH1, BH2 and BH3 domains of Bcl-2 and Bcl-x L . Fluorescence polarization studies indicated that affinity of HA14-1 for Bcl-2 was enhanced in the presence of UDCA. Moreover, Bcl-2 photodamage was promoted by UDCA using a photosensitizing agent with affinity for the endoplasmic reticulum, a site of Bcl-2 localization. Fluorescence resonance energy transfer (FRET) studies revealed that the proximity of Bcl-2 to a hydrophobic photosensitizing agent embedded in liposomes was enhanced by UDCA. Since photodamage will occur only if a protein is in close contact with a photosensitizing agent, we propose that these findings support the hypothesis that UDCA causes a conformational change in Bcl-2, promoting HA14-1 binding and enhancing affinity for certain membrane-bound photosensitizers. Cell Death and Differentiation (2004) 11, 906-914. doi:10.1038/sj.cdd.4401433 Keywords: apoptosis; Bcl-2; CPO; NPe6; SnET2; photodynamic therapy (PDT)Abbreviations: CPO, 9-capronyloxy-tetrakis(methoxyethyl) porphycene; DCA, deoxycholic acid; DEVD-R110, asp-glu-valasp-rhodamine 110 (fluorogenic caspase-3 substrate); ER, endoplasmic reticulum; flu-Bak, 5-carboxyfluorecein coupled to the N terminus of a peptide GQVGRQLAIIGDDINR derived from the BH3 domain of Bak; HA14-1, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; HO342, Höchst dye HO33342; mTHPC, meta-(tetrahydroxyphenyl) chlorin; NPe6, N-aspartyl chlorin e6; P, fluorescence polarization value; PDT, photodynamic therapy; SnET2, tin etiopurpurin; UDCA, ursodeoxycholic acid.

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Tauroursodeoxycholic Acid Prevents Bax-Induced Membrane Perturbation and CytochromecRelease in Isolated Mitochondria

Cited by 107 publications

References 62 publications

Conditional Intestinal Lipotoxicity in Apobec-1-/- Mttp-IKO Mice

Conditional Intestinal Lipotoxicity in Apobec-1-/- Mttp-IKO Mice

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

A mechanism for the proapoptotic activity of ursodeoxycholic acid: effects on Bcl-2 conformation

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