Basal PPAR alpha inhibits bile acid metabolism adaptation in chronic cholestatic model induced by alpha-naphthylisothiocyanate

摘要

Cholestasis is one of the most challenging diseases to be treated in current hepatology. However little is known about the adaptation difference and the underlying mechanism between acute and chronic cholestasis. In this study, wild-type and Ppar alpha-null mice were orally administered diet containing 0.05% ANIT to induce chronic cholestasis. Biochemistry, histopathology and serum metabolome analysis exhibited the similar toxic phenotype between wild-type and Ppar alpha-null mice. Bile acid metabolism was strongly adapted in Ppar alpha-null mice but not in wild-type mice. The Shp and Fxr mRNA was found to be doubled in cholestatic Ppar alpha-null mice compared with the control group. Western blot confirmed the up-regulated expression of FXR in Ppar alpha-null mice treated with ANIT. Inflammation was found to be stronger in Ppar alpha-null mice than those in wild-type mice in chronic cholestasis. These data chain indicated that bile acid metabolism and inflammation signaling were different between wild-type and Ppar alpha-null mice developing chronic cholestasis, although their toxic phenotypes could not be discriminated. So basal Ppar alpha cross-talked with FXR and inhibited bile acid metabolism adaptation in chronic cholestasis.