ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy

Müllenbach, Roman; Bennett, Amanda J.; Tetlow, Natasha; Patel, Nishma; Hamilton, Gavin; Cheng, Floria; Chambers, Joanna E.; Howard, Robert; Taylor-Robinson, S.D.; Williamson, Catherine

doi:10.1136/gut.2004.058115

Cited by 149 publications

(102 citation statements)

References 48 publications

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“…Total RNA was extracted from mouse livers with the Trizol reagent (Invitrogen). cDNA was synthesized from total RNA with an oligo-dT [12][13][14][15][16][17][18] primer and Superscript II reverse transcriptase (Invitrogen). Realtime PCR measurements were performed at 60°C in a Lightcycler apparatus (Roche) with Lightcycler Faststart DNA Master Plus SYBR Green I (Roche).…”

Section: Methodsmentioning

confidence: 99%

“…13 Finally, it has been recently shown that mutations in ATP8B1 may also play a role in the etiology of intrahepatic cholestasis of pregnancy (ICP). 14,15 We have previously shown in mice that Atp8b1 is essential for maintaining the detergent-resistant properties of the canalicular membrane. 16 When challenged with bile salts, Atp8b1-deficient mice displayed enhanced extraction of cholesterol and ectoenzymes from the canalicular membrane.…”

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confidence: 99%

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ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity

et al. 2008

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Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1. Previously, we have shown in mice that Atp8b1 deficiency leads to enhanced biliary excretion of phosphatidylserine, and we hypothesized that ATP8B1 is a flippase for phosphatidylserine. However, direct evidence for this function is still lacking. In Saccharomyces cerevisiae, members of the Cdc50p/Lem3p family are essential for proper function of the ATP8B1 homologs. We have studied the role of two human members of this family, CDC50A and CDC50B, in the routing and activity of ATP8B1. When only ATP8B1 was expressed in Chinese hamster ovary cells, the protein localized to the endoplasmic reticulum. Coexpression with CDC50 proteins resulted in relocalization of ATP8B1 from the endoplasmic reticulum to the plasma membrane. Only when ATP8B1 was coexpressed with CDC50 proteins was a 250%-500% increase in the translocation of fluorescently labeled phosphatidylserine observed. Importantly, natural phosphatidylserine exposure in the outer leaflet of the plasma membrane was reduced by 17%-25% in cells coexpressing ATP8B1 and CDC50 proteins in comparison with cells expressing ATP8B1 alone. The coexpression of ATP8B1 and CDC50A in WIF-B9 cells resulted in colocalization of both proteins in the canalicular membrane. Conclusion: Our data indicate that CDC50 proteins are pivotal factors in the trafficking of ATP8B1 to the plasma membrane and thus may be essential determinants of ATP8B1-related disease. In the plasma membrane, ATP8B1 functions as a flippase for phosphatidylserine. Finally, CDC50A may be the potential ␤-subunit or chaperone for ATP8B1 in hepatocytes. (HEPATOLOGY 2008;47: 268-278.)

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity

et al. 2008

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“…BRIC1 is characterized by periodic bouts of cholestasis, the onset and resolution of which are caused by unknown factors, and leaves no liver damage. Recently it was shown that mutations in ATP8B1 also are associated with intrahepatic cholestasis of pregnancy (2,3). The gene involved in these diseases, ATP8B1, encodes a member of the P4 subfamily of the P-type ATPase superfamily (4,5).…”

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confidence: 99%

Activity of the Bile Salt Export Pump (ABCB11) Is Critically Dependent on Canalicular Membrane Cholesterol Content

Paulusma¹,

Waart²,

Kunne

et al. 2009

Journal of Biological Chemistry

107

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Mutations in ATP8B1 cause severe inherited liver disease. The disease is characterized by impaired biliary bile salt excretion (cholestasis), but the mechanism whereby impaired ATP8B1 function results in cholestasis is poorly understood. ATP8B1 is a type 4 P-type ATPase and is a flippase for phosphatidylserine. Atp8b1-deficient mice display a dramatic increase in the biliary extraction of cholesterol from the canalicular (apical) membrane of the hepatocyte. Here we studied the hypothesis that disproportionate cholesterol extraction from the canalicular membrane impairs the activity of the bile salt transporter, ABCB11, and as a consequence causes cholestasis. Using single pass liver perfusions, we show that not only ABCB11-mediated transport but also Abcc2-mediated transport were reduced at least 4-fold in Atp8b1 deficiency. We show that canalicular membranes of cholestatic Atp8b1-deficient mice have a dramatically reduced cholesterol to phospholipid ratio, i.e. 0.75 ؎ 0.24 versus 2.03 ؎ 0.71 for wild type. In vitro depletion of cholesterol from mouse liver plasma membranes using methyl-␤-cyclodextrin demonstrated a near linear relation between cholesterol content of the membranes and ATPdependent taurocholate transport. Abcc2-mediated transport activity was not affected up to 30% of membrane cholesterol depletion but declined to negligible levels at 70% of membrane cholesterol depletion. These effects were reversible as cholesterol repletion of the liver membranes completely restored Abcb11-and Abcc2-mediated transport. Our data demonstrate that membrane cholesterol content is a critical determinant of ABCB11/ABCC2 transport activity, provide an explanation for the etiology of ATP8B1 disease, and suggest a novel mechanism protecting the canalicular membrane against luminal bile salt overload.

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“…The study also included electron microscopy of liver tissue and the alteration in the phospholipid component was judged to be related to a change in biliary phospholipid excretion in these cholestatic patients [37] . Such an increase in the in vivo PDE resonance, seen in the in vivo hepatic MR spectrum is not a specific finding in patients with chronic allograft rejection, because a similar, albeit less marked change has been found in patients with primary biliary cirrhosis and obstetric cholestasis [38,39] .…”

Section: Orthotopic Liver Transplantationmentioning

confidence: 98%

Current and future applications ofin vitromagnetic resonance spectroscopy in hepatobiliary disease

Cox

Sharif²,

Cobbold³

et al. 2006

WJG

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Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro . Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiological processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo . This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response.

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ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy

Cited by 149 publications

References 48 publications

ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity

ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity

Activity of the Bile Salt Export Pump (ABCB11) Is Critically Dependent on Canalicular Membrane Cholesterol Content

Current and future applications ofin vitromagnetic resonance spectroscopy in hepatobiliary disease

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