Journal of Biological Chemistry
Volume 279, Issue 7, 13 February 2004, Pages 5821-5828
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Mechanisms of Signal Transduction
Deoxycholic Acid Activates the c-Jun N-terminal Kinase Pathway via FAS Receptor Activation in Primary Hepatocytes: ROLE OF ACIDIC SPHINGOMYELINASE-MEDIATED CERAMIDE GENERATION IN FAS RECEPTOR ACTIVATION*

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We have shown previously that bile acids can activate the JNK pathway and down-regulate cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the neutral pathway of bile acid biosynthesis. In this study, the mechanism(s) by which deoxycholic acid (DCA) activates the JNK pathway were examined. FAS receptor (FAS-R) and acidic sphingomyelinase (ASM)-deficient hepatocytes were resistant to DCA-induced activation of the JNK pathway. Activation of the JNK pathway (2-3-fold) in response to tumor necrosis factor-α was similar in both wild-type and FAS-R-/- hepatocytes. In wild-type and FAS-R-/- hepatocytes, ceramide elevation was detected as early as 2 min and peaked at 10 min after DCA treatment. In contrast, ASM-/- hepatocytes were defective in DCA-induced ceramide generation. Treatment with DCA resulted in movement of FAS-R to the cell surface, which was blocked upon treatment with brefeldin A. However, brefeldin A failed to block DCA-mediated JNK activation in wild-type hepatocytes. DCA-induced JNK activation was independent of either the epidermal growth factor receptor activation or free radical generation. Addition of ASM to rat hepatocytes activated JNK and down-regulated CYP7A1 mRNA levels. In conclusion, these results show that DCA activates JNK and represses CYP7A1 mRNA levels in primary hepatocytes via an ASM/FAS-R-dependent mechanism that is independent of either the epidermal growth factor receptor or free radical generation.

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This work was supported by National Institutes of Health Grants PO1-DK38030 and RO1-DK52825, National Research Service Award 1 F32 DK59770-01 (to S. G.), and Department of Defense Career Development Award BC98-0148 (to P. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.