Pathological implications of cadherin zonation in mouse liver

Abstract

Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, β-catenin, which links both cadherins via α-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or α1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.

Segregated hepatocyte proliferation and metabolic states within the regenerating mouse liver

“…At 48 hours, the E-cadherin staining became more robust while maintaining its periportal pattern, as noted previously after a milder 30% PH protocol. (36) Here, mitotic figures were centered around the interface of the E-cadherin-positive and E-cadherinnegative regions, consistent with their primarily midlobular position, with both E-cadherin-positive and Ecadherin-negative hepatocytes displaying mitotic figures. (A metabolic periportal marker, PEPCK, also maintained its resting state periportal localization pattern at 48 hours after PH [Supporting Fig.…”

“…1. PH was performed as described (17) at ZT2, and livers were collected at 0, 1,4,10,20,24,28,36,44,48,60, and 72 hours and at 1 and 4 weeks after surgery. Additionally, to monitor the contribution of the surgical intervention other than liver resection, we performed a series of "sham" surgeries (labeled S in Fig.…”

“…5A) and thus suggests that these nonproliferating hepatocytes maintain normal functions of the liver. To probe the structural and metabolic states of the nonproliferating hepatocytes further, we respectively examined the staining pattern of (i) the adherens junction component E-cadherin, which is specific to PV proximal hepatocytes and mimics the pattern of periportal metabolic markers (36,37) (Fig. 7A), and (ii) GS, which is specific for pericentral hepatocytes (38,39) (Fig.…”

Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model

“…1A, HE). We have shown previously that cell adhesion contacts were disrupted during liver injury by the impairment of E-cadherin expression 26 . This was corroborated in the present study showing that the integrity of E-cadherin expression was disturbed in resected as compared with sham animals (Fig.…”

Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

“…Consistent with this finding, CDH1 expression was previously found altered in PiZ mice. (29) In contrast to wild-type livers, (28) CDH1 was detected in pericentral areas in addition to the reduced signal intensity in periportal areas (Fig. 3A).…”