To further determine the functional role of RanBP2-mediated SUMOylation of SHP, we challenged mice expressing SHP-WT or the SUMO-defective K68R mutant by either chronic BA feeding or by a more potent biliary insult, treatment with α-naphthyl isothiocyanate (ANIT), which induces intrahepatic cholestasis by injuring biliary epithelial cells31, 32. This evidence concerns the gene RANBP2 and intrahepatic cholestasis.