Liver Zonation Occurs Through a β-Catenin-Dependent, c-Myc-Independent Mechanism

Abstract

Background and Aims: The Wnt pathway has previously been shown to play a role in hepatic zonation. Herein, we have explored the role of 3 key components (Apc, β-catenin, and c-Myc) of the Wnt pathway in the zonation of ammonia metabolizing enzymes. Methods: Conditional deletion of Apc, β-catenin, and c-Myc was induced in the livers of mice and the expression of periportal and perivenous hepatocyte markers was determined by polymerase chain reaction, Western blotting, and immunohistochemical techniques. Results: Under normal circumstances, the urea cycle enzyme carbamoylphosphate synthetase I (CPS I) is present in the periportal, intermediate, and the first few layers of the perivenous zone. In contrast, glutamine synthetase (GS)-and nuclear β-catenin-is expressed in a complementary fashion in the last 1-2 cell layers of the perivenous zone. Conditional loss of Apc resulted in the expression of nuclear β-catenin and GS in most hepatocytes irrespective of zone. Induction of GS in hepatocytes outside the normal perivenous zone was accompanied by a reduction in the expression of CPS I. Deletion of β-catenin induces a loss of GS and a complementary increase in expression of CPS I irrespective of whether Apc is present. Remarkably, deletion of c-Myc did not perturb the pattern of zonation. Conclusions: It has been shown that the Wnt pathway is key to imposing the pattern of zonation within the liver. Herein we have addressed the relevance of 3 major Wnt pathway components and show critically that the zonation is c-Myc independent but β-catenin dependent. © 2009 AGA Institute.