Down-regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway.

Content Provider	Semantic Scholar
Author	Gupta, Shona Stravitz, Richard Todd Dent, Paul Hylemon, Phillip B.
Copyright Year	2001
Abstract	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.
Starting Page	76
Ending Page	84
Page Count	9
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.jbc.org/content/276/19/15816.full.pdf
PubMed reference number	11278771v1
Volume Number	276
Issue Number	19
Journal	The Journal of biological chemistry
Language	English
Access Restriction	Open
Subject Keyword	Anabolism Bile Acid Biosynthesis Pathway Bile Acids Bile fluid Biomarkers, Tumor CYP7A1 gene CYP7A1 protein, human Cholesterol 7-alpha-Monooxygenase Gene Expression Hepatocyte JUN gene Ligands MAPK8 gene Mixed Function Oxygenases NR1H4 gene NR1H4 wt Allele PTPN6 wt Allele Repression, Psychology Steroid 16-alpha-Hydroxylase Taurocholate Transcription, Genetic Tumor Necrosis Factors
Content Type	Text
Resource Type	Article