Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

Cecilia M.P. Rodrigues; Xiaoming Ma; Cheryle Linehan-Stieers; Guangsheng Fan; Betsy T. Kren; Clifford J Steer

doi:10.1038/sj.cdd.4400560

Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

Cecilia M.P. Rodrigues
, Xiaoming Ma
, Cheryle Linehan-Stieers
, Guangsheng Fan
, Betsy T. Kren
, Clifford J Steer

Research output: Contribution to journal › Article › peer-review

244 Scopus citations

Abstract

The hydrophilic bile salt ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis. In this paper, we further characterize the mechanism by which UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and transforming growth factor β1 in primary rat hepatocytes. Our data indicate that coincubation of cells with UDCA and each of the apoptosis-inducing agents was associated with an approximately 80% inhibition of nuclear fragmentation (P < 0.001). Moreover, UDCA prevented mitochondrial release of cytochrome c into the cytoplasm by 70-75% (P < 0.001), thereby, inhibiting subsequent activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) polymerase. Each of the apoptosis-inducing agents decreased mitochondrial transmembrane potential and increased mitochondrial-associated Bax protein levels. Coincubation with UDCA was associated with significant inhibition of these mitochondrial membrane alterations. The results suggest that the mechanism by which UDCA inhibits apoptosis involves an interplay of events in which both depolarization and channel-forming activity of the mitochondrial membrane are inhibited.

Original language	English (US)
Pages (from-to)	842-854
Number of pages	13
Journal	Cell Death and Differentiation
Volume	6
Issue number	9
DOIs	https://doi.org/10.1038/sj.cdd.4400560
State	Published - Sep 1999

Bibliographical note

Funding Information:
The authors thank all members of the laboratory for their comments and encouragement during the course of this work. This work was supported in part by a grant from the Minnesota Medical Foundation to CJ Steer, and by Postdoctoral Fellowhip PRAXIS XXI/BPD/11849/97 and grant PRAXIS/C/SAU/14311/1998 from FundacËaÄo para a CieÃncia e a Technologia, Lisbon, Portugal to CMP Rodrigues.

Keywords

Bax
Bile acid
Cytochrome c
Mitochondria
Permeability transition

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10.1038/sj.cdd.4400560

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title = "Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation",

abstract = "The hydrophilic bile salt ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis. In this paper, we further characterize the mechanism by which UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and transforming growth factor β1 in primary rat hepatocytes. Our data indicate that coincubation of cells with UDCA and each of the apoptosis-inducing agents was associated with an approximately 80\% inhibition of nuclear fragmentation (P < 0.001). Moreover, UDCA prevented mitochondrial release of cytochrome c into the cytoplasm by 70-75\% (P < 0.001), thereby, inhibiting subsequent activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) polymerase. Each of the apoptosis-inducing agents decreased mitochondrial transmembrane potential and increased mitochondrial-associated Bax protein levels. Coincubation with UDCA was associated with significant inhibition of these mitochondrial membrane alterations. The results suggest that the mechanism by which UDCA inhibits apoptosis involves an interplay of events in which both depolarization and channel-forming activity of the mitochondrial membrane are inhibited.",

keywords = "Bax, Bile acid, Cytochrome c, Mitochondria, Permeability transition",

author = "Rodrigues, \{Cecilia M.P.\} and Xiaoming Ma and Cheryle Linehan-Stieers and Guangsheng Fan and Kren, \{Betsy T.\} and Steer, \{Clifford J\}",

note = "Funding Information: The authors thank all members of the laboratory for their comments and encouragement during the course of this work. This work was supported in part by a grant from the Minnesota Medical Foundation to CJ Steer, and by Postdoctoral Fellowhip PRAXIS XXI/BPD/11849/97 and grant PRAXIS/C/SAU/14311/1998 from Fundac{\"E}a{\"A}o para a Cie{\~A}ncia e a Technologia, Lisbon, Portugal to CMP Rodrigues.",

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doi = "10.1038/sj.cdd.4400560",

language = "English (US)",

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AU - Rodrigues, Cecilia M.P.

AU - Ma, Xiaoming

AU - Linehan-Stieers, Cheryle

AU - Fan, Guangsheng

AU - Kren, Betsy T.

AU - Steer, Clifford J

N1 - Funding Information: The authors thank all members of the laboratory for their comments and encouragement during the course of this work. This work was supported in part by a grant from the Minnesota Medical Foundation to CJ Steer, and by Postdoctoral Fellowhip PRAXIS XXI/BPD/11849/97 and grant PRAXIS/C/SAU/14311/1998 from FundacËaÄo para a CieÃncia e a Technologia, Lisbon, Portugal to CMP Rodrigues.

PY - 1999/9

Y1 - 1999/9

N2 - The hydrophilic bile salt ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis. In this paper, we further characterize the mechanism by which UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and transforming growth factor β1 in primary rat hepatocytes. Our data indicate that coincubation of cells with UDCA and each of the apoptosis-inducing agents was associated with an approximately 80% inhibition of nuclear fragmentation (P < 0.001). Moreover, UDCA prevented mitochondrial release of cytochrome c into the cytoplasm by 70-75% (P < 0.001), thereby, inhibiting subsequent activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) polymerase. Each of the apoptosis-inducing agents decreased mitochondrial transmembrane potential and increased mitochondrial-associated Bax protein levels. Coincubation with UDCA was associated with significant inhibition of these mitochondrial membrane alterations. The results suggest that the mechanism by which UDCA inhibits apoptosis involves an interplay of events in which both depolarization and channel-forming activity of the mitochondrial membrane are inhibited.

AB - The hydrophilic bile salt ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis. In this paper, we further characterize the mechanism by which UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and transforming growth factor β1 in primary rat hepatocytes. Our data indicate that coincubation of cells with UDCA and each of the apoptosis-inducing agents was associated with an approximately 80% inhibition of nuclear fragmentation (P < 0.001). Moreover, UDCA prevented mitochondrial release of cytochrome c into the cytoplasm by 70-75% (P < 0.001), thereby, inhibiting subsequent activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) polymerase. Each of the apoptosis-inducing agents decreased mitochondrial transmembrane potential and increased mitochondrial-associated Bax protein levels. Coincubation with UDCA was associated with significant inhibition of these mitochondrial membrane alterations. The results suggest that the mechanism by which UDCA inhibits apoptosis involves an interplay of events in which both depolarization and channel-forming activity of the mitochondrial membrane are inhibited.

KW - Bax

KW - Bile acid

KW - Cytochrome c

KW - Mitochondria

KW - Permeability transition

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IS - 9

ER -

Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

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