Organic solute transporter (OSTalpha-OSTbeta) is a novel heteromeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney, and liver. To determine whether OSTalpha-OSTbeta undergoes farnesoid X receptor (FXR)-dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild-type mice. Hepatic OSTalpha and OSTbeta mRNA increased 3- and 32-fold, respectively, in patients with PBC compared with controls, whereas expression of Ostalpha and Ostbeta also increased in the liver of rats and mice following CBDL. In contrast, expression of Ostalpha and Ostbeta mRNA was generally lower in Fxr null mice, and CBDL failed to enhance expression of Ostalpha and Ostbeta compared with wild-type mice. HepG2 cells treated for 24 h with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OSTalpha and OSTbeta mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ostalpha and Ostbeta are highly regulated in response to cholestasis and that this response is dependent on the FXR bile acid receptor.

No abstract

Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding. However, the relative importance of Mrp4 in a protective adaptive response to cholestatic injury is not known. To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4؊/؊ mice and animals followed for 7 days. Histological analysis and serum aminotransferase levels revealed more severe liver injury in the absence of Mrp4 expression. Western analyses revealed that Mrp4, but not Mrp3, was significantly increased after CBDL in wild-type mice. Serum bile acid levels were significantly lower in Mrp4؊/؊ mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver. Mrp3 and Ost␣-Ost␤ were upregulated in Mrp4؊/؊ mice but were unable to compensate for the loss of Mrp4. High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4؊/؊ mice. In conclusion, hepatic Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic liver injury. ( M ultidrug resistance-associated protein 4 (MRP4) (ABCC4) is an ATP-dependent organic anion transporter with broad substrate specificity. [1][2][3] It is a member of the ABC transporter superfamily 4 and is expressed in a variety of epithelia, including the basolateral and apical plasma membranes of the liver and kidneys, respectively. 5-7 However, this array of substrates and specific tissue localization have not provided insight into Mrp4 function in vivo.Mrp4 was first suggested to play a role in the adaptive response to the hepatic overload of bile acids following the genetic deletion of farnesoid X receptor (FXR), a bile acid sensor. 8,9 A subsequent study suggested that Mrp4 was not elevated upon feeding the hydrophobic bile acid, lithocholic acid. 10 Despite this finding, other studies have demonstrated that hepatic Mrp4 is upregulated in both rats and mice after bile duct ligation 6,11 and in pediatric patients with progressive familial intrahepatic cholestasis. 12 Recent studies demonstrate that MRP4 functions as an efflux pump for bile acids together with glutathione. 13 Further support for a role for MRP4 in hepatic bile acid overload is the recent demonstration that Mrp4 is upregulated by the constitutive androstane receptor. 14 Constitutive androstane receptor is a member of the nuclear hormone receptor superfamily that is required to elevate serum bile acids during cholestatic injury. 15 Cholestatic injury in mice, rats, and humans can also result in adaptive responses in other basolateral transporters. Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodi...

Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

No abstract