Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTα-OSTβ in cholestasis in humans and rodents

Abstract

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.

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

“…OST/Ost␣-OST/Ost␤ expression also increases in response to CBDL (as confirmed in the present study) in the mouse and in patients with primary biliary cirrhosis. 17 Thus, induction of Mrp3 and OST/Ost␣-OST/Ost␤ is a reproducible finding in the cholestatic liver. However, our finding that there is more advanced cholestatic injury in Mrp4Ϫ/Ϫ mice after CBDL emphasizes that neither Mrp3 nor Ost␣-Ost␤ can fully compensate for the absence of Mrp4, even though both are fully capable of transporting bile acid conjugates.…”

“…12 Nevertheless, it is likely that Ost␣-Ost␤ plays a more prominent role in human liver rather than mouse liver, because this heterodimeric transport protein is more highly upregulated at the basolateral membrane of cholestatic human hepatocytes relative to changes in expression of Mrp3 and Mrp4. 17 Taurine Tetrahydroxy Bile Acid/Beta-Muricholic Acid Ratios Are Increased Twofold in Mrp4؊/؊ Mice Compared With Wild-Type Mice After CBDL. These differences in liver bile acid composition following CBDL are also consistent with greater cholestatic injury in Mrp4Ϫ/Ϫ mice, because the formation of tetrahydroxy bile acids represents an alternative pathway for detoxifying bile acids by phase 1 metabolism in the endoplasmic reticulum.…”

“…16,17 However, the relative importance of these basolateral transporters and their own particular role in responding to cholestatic stress in the liver are not well understood.…”

“…Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodimeric bile acid and organic solute transporter, Ost␣-Ost␤. 16,17 The relative contribution of Mrp4 in the protection against bile acid overload is unknown.…”

High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis #

“…Similar observations have been reported for patients with PBC and biliary atresia. 10,24,25 Expression of the phospholipid floppase ABCB4/ MDR3 is elevated in the liver of cholestatic patients. This may increase the amount of phosphatidylcholine that is available at the outer canalicular leaflet for mixed micelle formation and thus may represent an adaptive change favoring protection of downstream bile duct epithelium against bile salt toxicity.…”