Liver zonation occurs through a β-catenin–dependent, c-Myc–independent mechanism

Zoe D Burke, K R Reed, T J Phesse, O J Sansom, A R Clarke, David Tosh

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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.
Original languageEnglish
Pages (from-to)2316-2324e3
Number of pages9
JournalGastroenterology
Volume136
Issue number7
Early online date6 Mar 2009
DOIs
Publication statusPublished - Jun 2009

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