Abstract
Alpha-naphthyl isothiocyanate (ANIT) is a hepatotoxicant that produces acute intrahepatic cholestasis in rodents. Farnesoid X receptor (FXR) and pregnane X receptor (PXR) are two major bile acid sensors in liver. The purpose of this study was to characterize the regulation of hepatic transporters by FXR and PXR during ANIT-induced liver injury. Wild-type, FXR-null, and PXR-null mice were administered ANIT (75 mg/kg, po) and evaluated 48 h later for hepatotoxicity and messenger RNA (mRNA) expression of basolateral uptake (sodium taurocholate-cotransporting polypeptide, organic anion transporting polypeptide [Oatp] 1a1, Oatp1a4, Oatp1b2) and efflux transporters (organic solute transporter [Ost] alpha, Ostbeta, multidrug resistance-associated protein [Mrp] 3, Mrp4), as well as canalicular transporters (bile salt export pump [Bsep], Mrp2, multidrug resistance protein 2 [Mdr2], ATPase, class I, type 8B, member 1 [Atp8b1]). Livers from wild-type and PXR-null mice had comparable multifocal necrosis 48 h after ANIT. However, ANIT-treated FXR-null mice have fewer and smaller necrotic foci than wild-type mice but had scattered single-cell hepatocyte necrosis throughout the liver. Serum alanine transaminase, alkaline phosphatase (ALP), and direct bilirubin were increased in all genotypes, with higher ALP levels in FXR-null mice. Serum and liver unconjugated bile acids were higher in ANIT-treated FXR-null mice than the other two genotypes. ANIT induced mRNA expression of Mdr2, Bsep, and Atp8b1 in wild-type and PXR-null mice but failed to upregulate these genes in FXR-null mice. mRNA expression of uptake transporters declined in livers of all genotypes following ANIT treatment. ANIT increased Ostbeta and Mrp3 mRNA in livers of wild-type and PXR-null mice but did not alter Ostbeta mRNA in FXR-null mice. In conclusion, FXR deficiency enhances susceptibility of mice to ANIT-induced liver injury, likely a result of impaired induction of hepatobiliary efflux transporters and subsequent hepatic accumulation of unconjugated bile acids.
Highlights
Cholestasis is the disruption of bile flow that can occur at the cellular level of the hepatocyte, at the level of the intrahepatic biliary ductules, or as a result of extrahepatic obstruction of the bile ducts
This study demonstrates that Alpha-naphthyl isothiocyanate (ANIT)-induced liver injury results in the adaptive downregulation of hepatic uptake transporters and upregulation of efflux transporters in a timedependent pattern
Changes in transporter expression were most prominent at 48 h and correlated with activation of Farnesoid X receptor (FXR) and pregnane X receptor (PXR) signaling pathways
Summary
Cholestasis is the disruption of bile flow that can occur at the cellular level of the hepatocyte, at the level of the intrahepatic biliary ductules, or as a result of extrahepatic obstruction of the bile ducts. ANIT injures bile duct epithelium leading to cholestasis This liver injury is evident by detecting elevated serum bile acids and bilirubin, increased activities of aspartate aminotransferase, as well as histopathological lesions (Dahm et al, 1991). The expression of uptake transporters is reduced, and levels of efflux transporters are increased in damaged livers (Slitt et al, 2007; Trauner and Boyer, 2003). This adaptive response is thought to reduce the intracellular concentration of bile acids and other toxicants in an attempt to protect against further injury and promote cellular recovery
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