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Down-regulation of Cholesterol 7α-Hydroxylase (CYP7A1) Gene Expression by Bile Acids in Primary Rat Hepatocytes Is Mediated by the c-Jun N-terminal Kinase Pathway
Open accessAbstract
Cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the neutral pathway of bile acid biosynthesis, is feedback-inhibited at the transcriptional level by hydrophobic bile acids. Recent studies show that bile acids are physiological ligands for farnesoid X receptor (FXR). Activated FXR indirectly represses CYP7A1 transcription through induction of small heterodimer protein (SHP-1). In this study, we provide evidence that bile acids rapidly down-regulate CYP7A1 transcription via activation of the JNK/c-Jun pathway. Furthermore, we demonstrate that SHP-1 is also a direct target of activated c-Jun. In primary rat hepatocyte cultures, taurocholate (TCA) strongly activated JNK in a time- and concentration-dependent manner. Tumor necrosis factor-alpha, a potent activator of JNK, also rapidly activated JNK and down-regulated CYP7A1 mRNA levels. Overexpression of dominant-negative JNK1 or a transactivating domain mutant of c-Jun significantly blocked the ability of TCA to down-regulate CYP7A1 mRNA. In contrast, overexpression of wild-type c-Jun (c-Jun(wt)) enhanced the repression of CYP7A1 by TCA. Moreover, overexpression of c-Jun(wt) resulted in increased SHP-1 promoter activity. Mutation of a putative AP-1 (c-Jun) element suppressed c-Jun-mediated activation of the SHP-1 promoter construct. These results indicate that the bile acid-activated JNK pathway plays a pivotal role in regulating CYP7A1 levels in primary rat hepatocytes.
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Citations
Cites
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Self-citationNuclear Receptor-Dependent Bile Acid Signaling Is Required for Normal Liver Regeneration
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Metadata
- Authors
- Gupta, S., Stravitz, R. T., Dent, P., & Hylemon, P. B.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-05
- Volume
- 276
- Issue
- 19
- Pages
- 15816-15822
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1974993651
- Cited by
- 322
- References
- 2
- FWCI
- 23.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
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