The maintenance and generation of membrane polarity in hepatocytes

Abstract

H epatocytes, the major epithelial cells in the liver, are highly polarized. Their plasma membranes are separated by tight junctions into sinusoidalbasolateral and canalicular-apical domains, which contain distinct sets of proteins and lipids. A normal membrane polarity is vital for hepatocytes to perform many diverse functions, such as canalicular bile secretion and simultaneous sinusoidal secretion of large quantities of serum proteins into blood. Hepatocyte polarity is lost in many diseases like cholestasis. A complete understanding of the molecular mechanisms involved in hepatocyte polarity therefore is of considerable significance to both liver cell biology and the pathogenesis of liver diseases.To maintain the distinct distribution of proteins and lipids in the canalicular and sinusoidal membranes, hepatocytes have developed complex polarized trafficking and retention mechanisms. The establishment of membrane polarity in hepatocytes begins during liver embryogenesis. During hepatocyte differentiation, specific routes and mechanisms are defined for the delivery of plasma membrane proteins. How this polarity is maintained in adult hepatocytes and is generated during development are two major unanswered questions in this field.In this review, we first give an overview of the current knowledge about how membrane polarity is maintained in hepatocytes with the focus on recent developments in polarized protein trafficking. We then present a hypothetical model about how membrane polarity may be generated during liver development, and finally, we present an example of how membrane polarity is altered in cholestasis. Readers are directed to recent reviews for discussion of lipid trafficking in hepatocytes. 1,2

Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver

“…7 This difference might be explained by a limited sensitivity of the immunoelectronmicroscopic approach to detect small changes in carrier density in an area as 'large' as the pericanalicular area (defined as a 1 mm zone around the canaliculus) when compared to the amount of carriers in the apical membrane. However, this difference might also confirm observations indicating that Mrp2 is largely retained at the apical membrane in differentiated hepatic cells, while Bsep undergoes dynamic endocytosis and recycles between the canalicular membrane and a subapical region 17,35,36 The potential difference in the dynamics of these two carriers has been linked to differences in linkage to the actinbased cytoskeleton. While Mrp2 interacts via its PDZ domain with ezrin-radixin-moesin (ERM) proteins, 37 which bind directly to actin thereby providing a tight apical retention mechanism, Bsep does not contain a PDZ domain and does probably not interact with ERM proteins.…”

“…20 Thus, sorting of Mrp2 and Bsep may be differently regulated. 17 Therefore, we extended our previous immunoelectronmicroscopic investigation by studying density of Bsep in canalicular membranes (without microvilli), canalicular microvilli, and the pericanalicular zone of liver tissue of normal rat livers, rat livers made cholestatic by administration of TLCA and those treated with both, TLCA and TUDCA, identical to those reported recently. 7 …”

“…In addition, other factors such as protein membrane solubility may affect differences in carrier endocytosis. 17,18 Control TLCA TLCA+ TUDCA ) in the pericanalicular zone (1 mm), the canalicular membranes (without microvilli), and the microvilli of zone 2 hepatocytes in the isolated perfused rat liver. Livers were treated for 50 min with DMSO alone (0.1%, v/v, control), TLCA (10 mmol/l), or TLCA (10 mmol/l) þ TUDCA (25 mmol/l).…”

“…14,15 Thus, it remains unclear whether TUDCA modulates insertion of key apical carriers other than Mrp2 in cholestatic liver. Indeed, Bsep was shown recently to traffic directly from the Golgi to the canalicular domain 16,17 whereas targeting of Mrp2 is less clear: most apical proteins such as the pIgA receptor (pIgA-R) take a transcytotic route from the Golgi to the basolateral and then the apical membrane, 18 and Mrp2 has been localized in vesicles cotransporting pIgA-R. 19 In addition, Mrp2, but not Bsep, has been shown to be partially and reversibly relocated from the canalicular to the basolateral domain of hepatocytes after lipopolysacharide exposure. 20 Thus, sorting of Mrp2 and Bsep may be differently regulated.…”

The bile salt export pump

“…Short-term posttranscriptional regulation of Bsep There is considerable evidence from animal models that the canalicular localization of Bsep can be regulated by endo-and exocytotic mechanisms [4,96]. Studies in isolated perfused rat livers showed a stimulation of biliary excretion of bile salts concomitant with a stimulation of vesicular transport processes in hepatocytes [36].…”