SHP-independent mechanisms

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Bile acids are signaling molecules that have been shown to induce protein kinase C (PKC) and inhibit CYP7A1 gene expression via the cJun N-terminus kinase (JNK) pathway (Stravitz et al. 1995, 1996). Bile acids are known to induce inflammatory cytokines, TNFα and IL-1β, in hepatic macrophages (Kupffer cells). These cytokines may cross the sinusoid and inhibit CYP7A1 gene expression in hepatocytes (Miyake et al. 2000). The JNK pathway may regulate CYP7A1 gene expression in Shp null mice [148]. The downstream target of the JNK pathways in bile acid inhibition of CYP7A1 gene expression is not certain. The JNK pathway may lead to inactivation of HNF4α and inhibition of CYP7A1 gene transcription De Fabiani et al. 2001). It is possible that HNF4α is a primary target of JNK phosphorylation. It is known that HNF4α is phosphorylated by PKC, PKA, AMP kinase (AMPK), and tyrosine kinase to lower its DNA binding affinity and trans-activating activity. On the other hand, HNF4α is acetylated by histone acetyltransferase and is involved in pre-initiation complex assembly and chromatin remodeling (Soutoglou et al. 2000; Soutoglou and Talianidis 2002). Furthermore, FXR induces a fibroblast growth factor 19 (FGF19), which activates a surface fibroblast growth factor receptor 4 (FGFR4) signaling pathway leading to the inhibition of CYP7A1 via the JNK pathway (Holt et al. 2004). It should be noted that SHP is not involved in this FXR-dependent pathway. Preliminary results from this laboratory suggest that LCAactivated PXR binds to the BARE-I of the CYP7A1 promoter and inhibits CYP7A1 gene transcription by both SHP-dependent and -independent pathways. SHP interacts strongly with PXR in the presence of a PXR ligand and inhibits CYP7A1 gene transcription. PXR strongly interacts with HNF4α in a ligand-dependent manner. Interestingly PXR strongly interacts with PGC-1α in the absence of a PXR ligand. LCA specifically disrupted PXR and

PGC-1α interaction and resulted in inhibition of the CYP7A1 gene.

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