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Structural and functional hepatocyte polarity and liver disease.

Gissen P, Arias IM - J. Hepatol. (2015)

Bottom Line: Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus.However, the molecular mechanisms underlying these defects are not well understood.Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; UCL Institute of Child Health, London, UK; Great Ormond Street Hospital, London, UK. Electronic address: p.gissen@ucl.ac.uk.

No MeSH data available.


Related in: MedlinePlus

Protein defects in hepatocyte polarity disorders. Protein trafficking machinery proteins in yellow. VIPAR and VPS33B are associated with apical recycling endosome protein Rab11a (ARE). Unconventional motor Myosin 5b is associated with ARE and assists with trafficking along dynamic microtubules. Syntaxin 3 is a SNARE protein that acts as a docking site at the canalicular membrane. Tight junctional proteins TJP2 and Claudin1 (green) associated with a range of cholestasis syndromes. Apical membrane transporters (red) associated with inherited liver disorders include ABCB11, ABCB4, ATP8B1, ABCC2. Combined deficiency of basolateral organic anion transporters OATP1B1 and OATP1B3 (white) causes Rotor syndrome.
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f0030: Protein defects in hepatocyte polarity disorders. Protein trafficking machinery proteins in yellow. VIPAR and VPS33B are associated with apical recycling endosome protein Rab11a (ARE). Unconventional motor Myosin 5b is associated with ARE and assists with trafficking along dynamic microtubules. Syntaxin 3 is a SNARE protein that acts as a docking site at the canalicular membrane. Tight junctional proteins TJP2 and Claudin1 (green) associated with a range of cholestasis syndromes. Apical membrane transporters (red) associated with inherited liver disorders include ABCB11, ABCB4, ATP8B1, ABCC2. Combined deficiency of basolateral organic anion transporters OATP1B1 and OATP1B3 (white) causes Rotor syndrome.

Mentions: The RE component of the secretory pathway plays a critical role in apical as well as basolateral localization of various proteins [62]. This cargo-bearing structure contains a complex including one or more Rab protein GTPases and an actin-associated molecular motor, Myosin 5b, as well as adaptor proteins Rab11a, Fip1 and Fip2 as shown by the work in the MDCK cells [63]. Inhibition of Rab11a or Myosin 5b prevented polarization in WIF-B cells and primary hepatocytes and, when introduced into polarized cells, prompted depolarization and internalization of apical proteins [5]. These observations indicated that the RE is a major determinant of polarization not due to its ABC transporter cargo. Some of the endosome components which provide cues for apical membrane polarization have been previously characterized [64–68]. Mutations in MYO5B encoding Myosin 5b, which acts as a molecular motor not only for Rab11a, but also Rab11b, Rab25, and Rab8, cause MicroVillus Inclusion Disease (MVID) in which malabsorption results from the absence of the intestinal brush border [69]. Recent studies reveal that many patients with MYO5B mutations also manifest cholestasis and progressive liver disease [70]. Mouse Rab8 conditional knockouts mimic MVID; furthermore, patients with MVID without Myosin 5b defects were found to have mutations affecting Syntaxin 3, an apical membrane SNARE (family of membrane proteins that ensure fusion between opposing membranes), suggesting that Myosin 5b, Rab8, and Syntaxin 3 may be involved in the same trafficking pathway [71,72]. As the liver disease in mice with Rab8 deficiency or MVID patients with Syntaxin 3 defects has not been described thus far, it is possible that Rab8 and Syntaxin 3 role in this pathway is not as important in hepatocytes as it is in the intestine. Discovery of loss of function mutations in genes encoding RE-associated proteins such as Myosin 5b in MVID, VPS33B, and VIPAR in Arthrogryposis, Renal dysfunction and cholestasis syndrome (ARC) [73] supports the importance of the RE in establishment and maintenance of hepatocyte polarity (Fig. 6).


Structural and functional hepatocyte polarity and liver disease.

Gissen P, Arias IM - J. Hepatol. (2015)

Protein defects in hepatocyte polarity disorders. Protein trafficking machinery proteins in yellow. VIPAR and VPS33B are associated with apical recycling endosome protein Rab11a (ARE). Unconventional motor Myosin 5b is associated with ARE and assists with trafficking along dynamic microtubules. Syntaxin 3 is a SNARE protein that acts as a docking site at the canalicular membrane. Tight junctional proteins TJP2 and Claudin1 (green) associated with a range of cholestasis syndromes. Apical membrane transporters (red) associated with inherited liver disorders include ABCB11, ABCB4, ATP8B1, ABCC2. Combined deficiency of basolateral organic anion transporters OATP1B1 and OATP1B3 (white) causes Rotor syndrome.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582071&req=5

f0030: Protein defects in hepatocyte polarity disorders. Protein trafficking machinery proteins in yellow. VIPAR and VPS33B are associated with apical recycling endosome protein Rab11a (ARE). Unconventional motor Myosin 5b is associated with ARE and assists with trafficking along dynamic microtubules. Syntaxin 3 is a SNARE protein that acts as a docking site at the canalicular membrane. Tight junctional proteins TJP2 and Claudin1 (green) associated with a range of cholestasis syndromes. Apical membrane transporters (red) associated with inherited liver disorders include ABCB11, ABCB4, ATP8B1, ABCC2. Combined deficiency of basolateral organic anion transporters OATP1B1 and OATP1B3 (white) causes Rotor syndrome.
Mentions: The RE component of the secretory pathway plays a critical role in apical as well as basolateral localization of various proteins [62]. This cargo-bearing structure contains a complex including one or more Rab protein GTPases and an actin-associated molecular motor, Myosin 5b, as well as adaptor proteins Rab11a, Fip1 and Fip2 as shown by the work in the MDCK cells [63]. Inhibition of Rab11a or Myosin 5b prevented polarization in WIF-B cells and primary hepatocytes and, when introduced into polarized cells, prompted depolarization and internalization of apical proteins [5]. These observations indicated that the RE is a major determinant of polarization not due to its ABC transporter cargo. Some of the endosome components which provide cues for apical membrane polarization have been previously characterized [64–68]. Mutations in MYO5B encoding Myosin 5b, which acts as a molecular motor not only for Rab11a, but also Rab11b, Rab25, and Rab8, cause MicroVillus Inclusion Disease (MVID) in which malabsorption results from the absence of the intestinal brush border [69]. Recent studies reveal that many patients with MYO5B mutations also manifest cholestasis and progressive liver disease [70]. Mouse Rab8 conditional knockouts mimic MVID; furthermore, patients with MVID without Myosin 5b defects were found to have mutations affecting Syntaxin 3, an apical membrane SNARE (family of membrane proteins that ensure fusion between opposing membranes), suggesting that Myosin 5b, Rab8, and Syntaxin 3 may be involved in the same trafficking pathway [71,72]. As the liver disease in mice with Rab8 deficiency or MVID patients with Syntaxin 3 defects has not been described thus far, it is possible that Rab8 and Syntaxin 3 role in this pathway is not as important in hepatocytes as it is in the intestine. Discovery of loss of function mutations in genes encoding RE-associated proteins such as Myosin 5b in MVID, VPS33B, and VIPAR in Arthrogryposis, Renal dysfunction and cholestasis syndrome (ARC) [73] supports the importance of the RE in establishment and maintenance of hepatocyte polarity (Fig. 6).

Bottom Line: Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus.However, the molecular mechanisms underlying these defects are not well understood.Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; UCL Institute of Child Health, London, UK; Great Ormond Street Hospital, London, UK. Electronic address: p.gissen@ucl.ac.uk.

No MeSH data available.


Related in: MedlinePlus