Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein

Abstract

Intrahepatic cholestasis is often associated with impairment of biliary bile acid secretion, a process mediated by the sister of P-glycoprotein (Spgp or Abcb11) also known as the bile salt export pump (Bsep). In humans, mutations in the Spgp gene are associated with a fatal childhood disease, type 2 progressive familial intrahepatic cholestasis (PFIC2). However in mice, the "knockout" of Spgp only results in mild cholestasis. In this study, we fed spgp(-/-) knockout mice with a cholic acid (CA)-supplemented diet to determine whether a more pronounced PFIC2-like phenotype could be induced. Such mice developed severe cholestasis characterized by jaundice, weight loss, elevated plasma bile acid, elevated transaminase, cholangiopathy (proliferation of bile ductules and cholangitis), liver necrosis, high mortality, and wide-ranging changes in the mRNA expression of major liver genes (16/36 examined). A surprising observation was that the bile acid output and bile flow in CA-fed mutant mice was significantly higher than anticipated. This suggests that the spgp(-/-) mice are able to utilize an alternative bile salt transport system. However, unlike Spgp, this system is insufficient to protect the knockout mice from cholestasis despite its high capacity. In conclusion, the spgp(-/-) mice provide a unique model to investigate molecular pathways associated with cholestasis and related diseases.

The bile salt export pump

“…Unexpectedly, cholate-fed knockout mice secrete significant amounts of cholate conjugate into bile, indicating a salvage transport system for canalicular bile salt secretion. Comparative analysis of gene expression profiles in control and knockout-mice after cholate feeding revealed a striking upregulation of Mdr1a [98]. This observation may indicate that mouse Mdr1a could act as a salvage transporter for bile salts in conditions of high intracellular bile salt concentration.…”

“…The Bsep knockout animals have substantial increases of malondialdehyde levels in brain and heart, indicating an increased lipid peroxidation as a consequence of elevated serum bile acid levels [56]. If Bsep knockout animals are fed with a diet containing cholate, they become severely cholestatic and have a high mortality rate, which is more pronounced in males than females [98]. Unexpectedly, cholate-fed knockout mice secrete significant amounts of cholate conjugate into bile, indicating a salvage transport system for canalicular bile salt secretion.…”

Abcb11 Deficiency Induces Cholestasis Coupled to Impaired β-Fatty Acid Oxidation in Mice

“…S3D), indicating general down-regulation of bile acid synthesis. It is notable that most of these changes in gene expression have been reported in Abcb11 deficiency on either a mixed genetic background or FVB (9,23).…”

Recent insights into the function and regulation of the bile salt export pump (ABCB11)

“…For example, while taurolithosulfocholate is not transported by rat Bsep (24,76), it is a substrate of human BSEP (76). Furthermore, mice with an ablated Bsep gene do not develop severe cholestasis on a normal diet (77), but need to be put on a high cholate diet (78). As a consequence of absent Bsep, novel, more hydrophilic bile salts have been detected in the bile of knockout animals (77) as well as an upregulation of p-glyocoprotein, which could provide a salvage pathway for bile salts (79).…”