Got Bile?

Abstract

Mice lacking the nuclear receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wildtype mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular transport protein. Bile repression and induction of cholesterol 7␣-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor. COMMENTSThe synthesis and enterohepatic circulation of bile acids (BA) are tightly regulated processes, required for cholesterol elimination, stimulation of bile flow, and absorption of lipids from the intestine. 1 These key events in BA physiology are governed by specific proteins. The rate-limiting enzyme for conversion of cholesterol into BA is cholesterol 7␣ hydroxylase (CYP7A). BA secretion occurs via the bile salt export protein, termed BSEP. Once in the intestine, BA are reclaimed in the ileum via I-SBT, the ileal sodiumdependent BA transporter; finally, reuptake of BA from portal blood into hepatocytes occurs via the sodium/taurocholate cotransporter (NTCP). The critical importance of these proteins to BA homeostasis is evidenced by the fact that several neonatal cholestatic liver diseases and disorders of lipid malabsorption are caused by mutations in their encoded genes. 2 The accumulation of hydrophobic BA within hepatocytes contributes to liver injury in cholestatic diseases. 1 Displacement of these toxic BA by a hydrophilic BA, ursodeoxycholic acid (UDCA), slows progression of fibrosis in primary biliary cirrhosis (PBC). 3 The concentration of BA within the hepatocyte regulates BA synthesis and uptake in a negative feedback manner. The recent cloning and characterization of pertinent synthetic enzymes, BA transporters, and regulatory transcription factors has made possible a detailed analysis of the underlying molecular mechanisms. 2 In infants with biliary atresia, for example, hepatic expression of NTCP is suppressed in proportion to the degree of biliary obstruction and is reversible. 4 Similarly in cholestatic animals, there is down-regulation of ntcp with relative preservation of bsep expression. 5 The net effect of these changes in NTCP and BSEP expression is a reduction in intracellular levels of potentially toxic BA in cholestasis.A regulatory transcription factor, FXR, acts as the sensor that links intracellular BA levels to changes in hepatic gene transcription. 6 FXR belongs to the nuclear hormone receptor class of transcription factors, which activate target genes when bound by specific ligands. Gene activation is t...