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J. Biol. Chem., Vol. 275, Issue 26, 20210-20216, June 30, 2000
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From the Liver injury during cholestasis reflects a
balance between the effects of toxic and nontoxic bile acids. However,
the critical distinction between a toxic and nontoxic bile acid remains
subtle and unclear. For example, the glycine conjugate of
chenodeoxycholate (GCDC) induces hepatocyte apoptosis, whereas the
taurine conjugate (TCDC) does not. We hypothesized that the dissimilar
cellular responses may reflect differential activation of a
phosphatidylinositol 3-kinase (PI3K)-dependent signaling
pathway. In the bile acid-transporting McNtcp.24 rat hepatoma cell
line, TCDC, but not GCDC, stimulated PI3K activity. Consistent with
this observation, inhibition of PI3K rendered TCDC cytotoxic, and
constitutive activation of PI3K rendered GCDC nontoxic. Both Akt and
the atypical protein kinase C isoform
The Bile Acid Taurochenodeoxycholate Activates a
Phosphatidylinositol 3-Kinase-dependent Survival
Signaling Cascade*
,
,
Division of Gastroenterology and Hepatology,
the § Department of Oncology, the ¶ Division of
Infectious Diseases, and the ** Division of Internal Medicine and
Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905 and
the Centro de Biologia Molecular, Consejo Superior de
Investigaciones Científicas-Universidad Autonoma de Madrid,
Canto Blanco, 28049 Madrid, Spain
(PKC) have been implicated
in PI3K-dependent survival signaling. However, TCDC
activated PKC, but not Akt. Moreover, inhibition of PKC converted
TCDC into a cytotoxic agent, whereas overexpression of wild-type PKC
blocked GCDC-induced apoptosis. We also demonstrate that TCDC
activated nuclear factor 
B (NF-B) in a PI3K- and
PKC-dependent manner. Moreover, inhibition of NF-B by
an IB super-repressor rendered TCDC cytotoxic, suggesting that
NF-B is also necessary to prevent the cytotoxic effects of TCDC.
Collectively, these data suggest that some hydrophobic bile acids such
as TCDC activate PI3K-dependent survival pathways, which
prevent their otherwise inherent toxicity.
*
This work was supported by National Institutes of Health
Grants DK41876 (to G. J. G.), CA73622 (to L. M. K.), and AI36076 (to C. V. P.); Deutsche Forschungsgemeinschaft Grant Ru742/1-1 (to
C. R.); Comisión Interministerial de Ciencia y
Tecnología Grant SAF99-0053, DGICYT Grant PM96-0002-C02, and
European Union Grant BIO4-CT97-2071 (to J. M.); the Gainey Foundation,
St. Paul, MN; and the Mayo Foundation, Rochester, MN.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Mayo Medical
School, Clinic, and Foundation, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-0686; Fax: 507-284-0762; E-mail:
gores.gregory@mayo.edu.
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