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LIVER AND BILIARY TRACT

Cytokine regulation of human sterol 12-hydroxylase (CYP8B1) gene

Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio

Submitted 6 May 2004 ; accepted in final form 15 November 2004

Sterol 12-hydroxylase (CYP8B1) catalyzes cholic acid synthesis in the liver and is feedback inhibited by bile acids. In addition to activating farnesoid X receptor (nuclear receptor subfamily 1H4), bile acids also induce inflammatory cytokines in hepatocytes. The objective of this study was to investigate the mechanism by which inflammatory cytokines inhibit human CYP8B1 gene transcription. Real-time PCR assays revealed that both chenodeoxycholic acid (CDCA) and interleukin-1 (IL-1) markedly reduced CYP8B1, cholesterol 7-hydroxylase CYP7A1 and hepatic nuclear factor 4 (HNF4) mRNA expression levels in human primary hepatocytes. However, CDCA induced, but IL-1 reduced, small heterodimer partner (SHP) mRNA expression. IL-1 inhibited human CYP8B1 reporter activity only in liver cells, and a c-Jun NH₂-terminal kinase (JNK)-specific inhibitor-blocked IL-1 inhibition. Activated JNK1 or c-Jun inhibited, whereas their dominant negative forms blocked, IL-1 inhibition of CYP8B1 transcription. Mutagenesis analyses mapped an IL-1 response element to a previously identified bile acid response element, which contains an HNF4 binding site. A dominant negative HNF4 inhibited CYP8B1 gene transcription and ectopically expressed HNF4 blocked IL-1 inhibition. Furthermore, IL-1 inhibited HNF4 gene transcription, protein expression, and binding to the CYP8B1 gene. JNK1 phosphorylated HNF4 and a JNK-specific inhibitor blocked the IL-1 inhibition of HNF4 expression. These results suggest that IL-1 inhibits CYP8B1 gene transcription via a mitogen-activated protein kinase/JNK pathway that inhibits HNF4 gene expression and its DNA-binding ability. This mechanism may play an important role in the adaptive response to inflammatory cytokines and in the protection of the liver during cholestasis.

bile acid synthesis; nuclear receptor; interleukin-1; hepatic nuclear factor 4; cholestasis

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