ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function

P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe Cholestatic liver disease. Mutation of ATP8B1 cause progressive familial Intrahepatic Cholestasis type 1 (PFIC1)and benign recurrent intrahepatic cholestasis type 1 (BRIC 1). From our observations we hypothesized that ATP8B1 deficiency causes a phospholipids randomization at the canalicular membrane, which results in extraction of cholesterol due to increase sensitivity of the canalicular membrane. Deficiency of ATP11C causes conjugated hyperbilirubinemia. In our preliminary result we observed accumulation of unconjugated bile salts in Atp11c deficient mice probably because of regulation in the expression or function of OATP1B2. Similar to ATP8B1, ATP11C have regulation on membrane transporters.

[1]  C. Paulusma,et al.  The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. , 2014, Biochimica et biophysica acta.

[2]  J. Sprent,et al.  ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes , 2011, Nature Immunology.

[3]  B. Beutler,et al.  X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C , 2011, Proceedings of the National Academy of Sciences.

[4]  B. Beutler,et al.  The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow , 2011, Nature Immunology.

[5]  F. Suchy,et al.  Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings. , 2011, Seminars in liver disease.

[6]  E. van de Steeg,et al.  Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs. , 2010, The Journal of clinical investigation.

[7]  Richard J. Thompson,et al.  Differences in presentation and progression between severe FIC1 and BSEP deficiencies. , 2010, Journal of hepatology.

[8]  C. Paulusma,et al.  Progressive familial intrahepatic cholestasis type 1. , 2010, Seminars in liver disease.

[9]  S. Strom,et al.  ATPase Class I Type 8B Member 1 and Protein Kinase C ζ Induce the Expression of the Canalicular Bile Salt Export Pump in Human Hepatocytes , 2010, Pediatric Research.

[10]  E. Krieger,et al.  Folding defects in P‐type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4‐phenylbutyrate , 2010, Hepatology.

[11]  Lieke M van der Velden,et al.  ATP8B1 is essential for maintaining normal hearing , 2009, Proceedings of the National Academy of Sciences.

[12]  C. Paulusma,et al.  Activity of the Bile Salt Export Pump (ABCB11) Is Critically Dependent on Canalicular Membrane Cholesterol Content , 2009, Journal of Biological Chemistry.

[13]  J. Boyer,et al.  ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. , 2009, Gastroenterology.

[14]  T. Miloh,et al.  The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor , 2008, Hepatology.

[15]  C. Paulusma,et al.  Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice. , 2008, Gastroenterology.

[16]  A. M. D. DE Tommaso,et al.  Partial internal biliary diversion through a cholecystojejunocolonic anastomosis--a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. , 2007, Journal of pediatric surgery.

[17]  L. Pawlikowska,et al.  Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport , 2006, Hepatology.

[18]  R. Houwen,et al.  FIC1 Is Expressed at Apical Membranes of Different Epithelial Cells in the Digestive Tract and Is Induced in the Small Intestine During Postnatal Development of Mice , 2004, Pediatric Research.

[19]  Richard J. Thompson,et al.  Characterization of mutations in ATP8B1 associated with hereditary cholestasis , 2004, Hepatology.

[20]  N. Freimer,et al.  A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. , 2004, Human molecular genetics.

[21]  Richard J. Thompson,et al.  Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. , 2004, Gastroenterology.

[22]  L. Klomp,et al.  Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. , 2003, Journal of hepatology.

[23]  L. Frulloni,et al.  Progressive familial intrahepatic cholestasis. , 2002, Acta bio-medica : Atenei Parmensis.

[24]  R. Houwen,et al.  FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. , 2001, Journal of hepatology.

[25]  N. Freimer,et al.  A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis , 1998, Nature Genetics.

[26]  S. Narumiya,et al.  Failure of parturition in mice lacking the prostaglandin F receptor. , 1997, Science.