Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice.

[zellweger syndrome]

The marked deficiency of peroxisomal organelle assembly in the PEX 2 (-/-) mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products . The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state . PEX 2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36 . We confirmed the expected reduction of mature C 2 4 bile acids , accumulation of C 2 7 -bile acid intermediates , and low total bile acid level in liver and bile from these mutant mice . Treating the PEX 2 (-/-) mice with bile acids prolonged postnatal survival , alleviated intrahepatic cholestasis and intestinal malabsorption , reduced C 2 7 -bile acid intermediate production , and prevented older mutants from developing severe steatohepatitis . However , this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver . Both untreated and bile acid-fed PEX 2 (-/-) mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters . Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX 2 mutants , indicating a generalized defect in bile acid conjugation .Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice , and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease .