SHP-dependent mechanism

From LipidomicsWiki

It is thought that bile acid-activated FXR induces an atypical, negative nuclear receptor, SHP, which subsequently interacts with FTF and inhibits CYP7A1 gene transcription (Lu et al. 2000; Goodwin et al. 2000). This cascade mechanism is supported by the lack of inhibition of CYP7A1 and induction of SHP mRNA expression by bile acid feeding in Fxr null mice (Sinal et al. 2000). Shp null mice fail to repress CYP7A1 in response to the FXR agonist, GW4064 as expected. Surprisingly, Shp null mice remain responsive to inhibition of CYP7A1 mRNA by bile acid feeding (Wang et al. 2002; Kerr et al. 2002). These mice have no severe phenotype and have only mild defects in bile acid synthesis. It is suggested that redundant pathways for bile acid inhibition of CYP7A1 may exist in Shp null mice, and the FXR agonist inhibits CYP7A1 via a SHP-dependent pathway (Wang et al. 2002). However, the SHPdependent mechanism suffers from the lack of specificity, because SHP is known to interact with most, if not all nuclear receptors. Being a negative regulator, SHP must be under a stringent control in vivo in order to prevent bile acids from inhibiting nuclear receptorregulated genes involved in liver development, differentiation and metabolism. This gene induction mechanism may be a response to massive accumulation of cytotoxic bile acids by bile acid feeding in rodents. It is not certain that this mechanism is a physiological

mechanism for bile acid feedback inhibition of bile acid synthesis in humans.

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