Inflammation Mediated Down-Regulation of Hepatobiliary Transporters Contributes to Intrahepatic Cholestasis and Liver Damage in Murine Biliary Atresia

Abstract

ABSTRACT:To investigate the hypothesis that during the development of biliary atresia, early changes in hepatobiliary transport are mainly related to the inflammatory process and lead to intrahepatic cholestasis and subsequent liver injury, livers from mice with rhesus rotavirus-induced biliary atresia were analyzed for mRNA expression of hepatobiliary transporters, nuclear receptors, and inflammatory cytokines. Seven days after inoculation, despite high bile acid concentrations in the liver, gene expression of canalicular and basolateral hepatobiliary transporters and their regulatory nuclear receptors was down-regulated with concomitant increase in gene expression of inflammatory cytokines and rise in serum unconjugated bilirubin. At 14 d, hepatobiliary transporters and nuclear receptors remained down-regulated although the inflammatory response subsided. The percentage of conjugated bilirubin started to increase as extrahepatic biliary obstruction occurred. At 18 d, expression of hepatobiliary transporters remained low, expression of nuclear receptors returned to normal, while expression of inflammatory cytokines decreased further. Moreover, histology demonstrated progressive inflammation, bile duct damage, ductular proliferation, and hepatocyte necrosis. In conclusion, intrahepatic cholestasis due to inflammation-related down-regulation of basolateral and canalicular hepatobiliary transporters is an early event in the development of biliary atresia. Intrahepatic cholestasis contributes to the development of jaundice and liver injury. (Pediatr Res 66: 380-385, 2009)

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

“…Observed increases in basolateral expression of Abcc3 and Abcc1 likely served to shuttle excess bile acids from hepatocytes into maternal blood. The changes in expression of these transporters and increased serum bile acids are consistent with other animal models of inflammation-induced cholestasis (Vos et al, 1998;McGillicuddy et al, 2009;Yang et al, 2009;Kosters and Karpen, 2010). It is believed that increased expression of basolateral efflux transporters is a homeostatic mechanism evoked to protect hepatocytes (Wagner et al, 2009;Keppler, 2011).…”

Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2

“…SP functions as a neurotransmitter and inflammatory mediator and is also involved in the regulation of bile secretion, biliary dynamics and liver innervations. A role for hepatobiliary transporters (particularly Fxr) in murine BA has recently been reported (33).…”

Impact of Polyinosinic/Polycytidylic Acid on Placental and Hepatobiliary Drug Transporters in Pregnant Rats

“…Increased levels of total bile acids have been reported in pregnant rats with obstructive cholestasis (Hassan and Subbiah, 1980;Serrano et al, 2003). Likewise, studies in cholestatic nonpregnant rodents also reported an increase in total bile acids Yang et al, 2009). Repeated poly(I:C) administration over 28 weeks has been reported to induce the development of primary biliary cirrhosis in mice (Okada et al, 2005); however, it is unknown whether single doses of poly(I:C) can induce cholestasis.…”

“…Furthermore, bilirubin accumulation may be a slower process than changes in accumulation of bile acids. Indeed, a recent study has shown that bile salt levels in the liver were profoundly higher in infected mice much sooner than the onset of direct hyperbilirubinemia (Yang et al, 2009). Studies of duration longer than 24 h may be helpful in clarifying the regulation of bilirubin during maternal infections.…”

“…Previous studies have demonstrated that an acute inflammatory response induced by bacterial endotoxin [lipopolysaccharide (LPS)] down-regulates the expression and activity of key ABC transporters in rodent liver, brain, renal, intestinal, and placental tissues with a corresponding change in drug disposition (for review, see Petrovic et al, 2007;Morgan et al, 2008). In addition, other disease models associated with inflammation, such as induced chronic renal failure, diabetes, cholestasis, or cancer, have been shown to modulate the hepatic expression of several transporters (Slaviero et al, 2003;Teng and Piquette-Miller, 2007;Nolin et al, 2008;Anger et al, 2009;Yang et al, 2009).…”