Loss of hepatocyte Usp53 protects mice from a form of xenobiotic-induced liver injury

Background: Ubiquitin-specific protease 53 (USP53) deficiency is associated with familial intrahepatic cholestasis in which serum gamma-glutamyl transferase (GGT) activity is relatively low. However, how USP53 deficiency contributes to cholestasis is obscure. No animal model has been reported.

Methods: Usp53 liver-specific knockout (Usp53 cKO) mice generated by crossing Usp53^fl/fl mice with albumin-cre (Alb-cre) recombinase transgenic mice were challenged with dietary cholic acid (CA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). General well-being, hepatobiliary-injury biomarker values, histopathologic and ultrastructural appearances, and expression of key genes were compared with those in wild-type (WT) littermates. Interactions of USP53 and TJP2 were investigated by immunofluorescence and co-immunoprecipitation.

Results: Usp53 cKO mice exhibited no obvious differences from WT mice when fed with either normal-chow or CA-added diet. However, after 4 weeks of DDC feeding, Usp53 cKO mice lost less weight, were less icteric, had more nearly normal biomarker values, and accumulated less intrahepatic pigment than WT mice. On normal chow, mRNA expression of critical hepatic transporters Abcb11, Ntcp, and Abcc2 was lower in Usp53 cKO liver than in WT liver; after DDC feeding, mRNA expression of Tjp2 was higher, while detoxification enzymes Cyp3a11, Cyp2b10, and Sult2a1 was lower in Usp53 cKO liver than in WT liver, and hepatocellular tight junctions were significantly longer. USP53 interacts with TJP2.

Conclusions: Usp53 deficiency can protect mice from DDC-induced liver injury. Liver Usp53 cKO causes upregulation of hepatobiliary Tjp2, with biochemical and histologic features that largely mimic those of liver Tjp2 cKO, implying that USP53 deficiency may share similar mechanism to TJP2 deficiency.