Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in theabcb11^−/−mouse: transport and gene expression studies

Abstract

The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice ( abcb11 −/−) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11−/− mice. Feeding UDCA to abcb11−/− mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11−/− mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11−/− mice. UDCA fed to abcb11−/− mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11−/− mice.

Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways

“…NBD-UDCA is secreted into BC by membrane transporters, mainly BSEP 55 . After washing, the cells were treated for 2 h and imaging was performed using an inverted microscope (Zeiss Axiovert 200 M and AxioCam MRm).…”

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

“…After experimental ligation of the common bile duct, tetrahydroxy and even pentahydroxy C 24 bile acids occur in the plasma and urine of mice ( 115 ). Such bile acids also occur in mice when the canalicular bile salt export pump (BSEP) has been deleted genetically ( 116 ). been prepared synthetically and some its biological properties explored ( 108 ).…”

“…Second, in mice, MDR1 is upregulated and is likely to be an effective conjugated bile acid extruder ( 274 ). Third, BSEP-deficient mice form tetra-hydroxy and penta-hydroxy bile acids ( 275,276 ), some or all of which are likely to be transported by MRP2 ( 277 ). Humans with cholestatic liver disease do not form tetra-or penta-hydroxy bile acids to any extent.…”

Impaired Hepatic Phosphatidylcholine Synthesis Leads to Cholestasis in Mice Challenged With a High‐Fat Diet

“…Biliary PC is essential for the protection of cells lining the biliary tree from the cytotoxic actions of high concentrations of biliary BA . BAs, which are exclusively synthesized from cholesterol in the liver, are secreted into bile by the bile salt export protein (BSEP; also known as adenosine triphosphatase [ATPase] binding cassette subfamily B member 11 [ABCB11]), PC by the flippase ABCB4/multidrug resistance 2 (MDR2), and cholesterol by the ABCG5/ABCG8 heterodimer . ATPase phospholipid transporting 8B1 (ATP8B1) maintains phospholipid asymmetry of the canalicular membrane that is essential for hepatobiliary transport.…”