Complementary Functions of the Flippase ATP8B1 and the Floppase ABCB4 in Maintaining Canalicular Membrane Integrity

Groen, A.K.; Romero, Marta R.; Kunne, Cindy; Hoosdally, Sarah; Dixon, Peter H.; Wooding, C; Williamson, Catherine; Seppen, Jurgen; Oever, Karin van den; Mok, King-Tong; Paulusma, Coen C.; Linton, Kenneth J.; Elferink, Ronald P.J. Oude

doi:10.1053/j.gastro.2011.07.042

Cited by 109 publications

(108 citation statements)

References 25 publications

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“…According to our results, comparable changes have been reported in the bile of Mdr2 wild-type and KO mice during intravenous infusion with increasing amounts of taurocholate: 25,28 a simultaneous increase of PC and Chol was documented in the wild-type animals, whereas an inverted PC/Chol ratio was observed in the KO.…”

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiosupporting

confidence: 89%

“…As already demonstrated, 25 the expression of ABCB4 wild type may be detrimental to the vitality of the cell. In fact, even if both mutant cell lines show deficiency of floppase activity, curiously the relative fold increase in PC secretion, upon NaTC treatment, appears very similar or higher in the mutants compared with the wild type.…”

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiomentioning

confidence: 70%

“…As for the latter case, simple heterozygous genotypes with ABCB4 mutation are considered a genetic susceptibility factor, resulting in disease only if concomitant risk factors are associated. 14,25 A substantial deficit of the floppase activity has been also predicted for both mutations because they are located within two structural motifs of the N-terminal NBD involved in ATP hydrolysis, as suggested by the homology model of MDR3 built on the crystal structure of the homologous murine multidrug resistance protein 1A. These motifs represent invariant loci from bacteria to man.…”

Section: Discussionmentioning

confidence: 96%

“…Recently, Groen et al 25 have shown a functional interdependence between MDR3-floppase activity (that promotes outward translocation of inner leaflet PC) and ATP8B1-flippase activity (that promotes inward translocation of outer leaflet phosphatidylserine); only the concerted activities of both transporters allow the necessary balance of phospholipids through the bilayer of the hepatocanalicular membrane. Moreover, this 'lipid asymmetry' , a mechanism that ensures protection of hepatocytes against the detergent action of bile salts, needs to be maintained in an active mode through MDR3 function, as the formation of nontoxic bile (i.e, of mixed bile salt micelles-PC-Chol where bile salt detergent activity is reduced) is ensured by the continuous excretion of PC into the canalicular lumen by bile salts.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon could be explained by the concept of rupture of the 'lipid asymmetry' , caused by the ABCB4 mutations, indicating that a severe alteration of floppase activity only, in a context where flippase activity is maintained to wild-type levels, could prevent the appropriate phospholipidic gradient across the canalicular membrane that is necessary to protect from detergent properties of toxic bile. 25 The passive extraction of Chol from the outer leaflet of the plasma membrane, mediated by NaTC not complexed with an appropriates amount of PC, is hence plausible.…”

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiomentioning

confidence: 99%

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Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

et al. 2013

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The ABCB4 gene encodes for MDR3, a protein that translocates phosphatidylcholine from the inner to the outer leaflet of the hepatocanalicular membrane; its deficiency favors the formation of 'toxic bile'. Several forms of hepatobiliary diseases have been associated with ABCB4 mutations, but the detrimental effects of most mutations on the encoded protein needs to be clarified. Among subjects with cholangiopathies who were screened for mutations in ABCB4 by direct sequencing, we identified the new mutation p.(L481R) in three brothers. According to our model of tertiary structure, this mutation affects the Q-loop, whereas the p.(Y403H) mutation, that we already described in two other families, involves the A-loop. This study was aimed at analyzing the functional relevance of these two ABCB4 mutations: MDR3 expression and lipid content in the culture supernatant were evaluated in cell lines stably transfected with the ABCB4 wild-type clone and corresponding mutants. No differences of expression were observed between wild-type and mutant gene products. Instead, both mutations caused a reduction of phosphatidylcholine secretion compared with the wild-type transfected cell lines. On the contrary, cholesterol (Chol) release, after 1 and 3 mM sodium taurocholate stimulation, was higher in the mutant-transfected cell lines than that in the wild-type and was particularly enhanced in cells transfected with the p.Y403H-construct.In summary, our data show that both mutations do not seem to affect protein expression, but are able to reduce the efflux of phosphatidylcholine associated with increase of Chol, thereby promoting the formation of toxic bile.

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Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiosupporting

confidence: 89%

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiomentioning

confidence: 70%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiomentioning

confidence: 99%

See 3 more Smart Citations

Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

et al. 2013

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Liver Function in Health and Disease

Mells

Alexander²

2018

Sherlock's Diseases of the Liver and Biliary System

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Bile Formation and Secretion

Boyer

2013

Comprehensive Physiology

678

602

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Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.

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Complementary Functions of the Flippase ATP8B1 and the Floppase ABCB4 in Maintaining Canalicular Membrane Integrity

Cited by 109 publications

References 25 publications

Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

Liver Function in Health and Disease

Bile Formation and Secretion

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