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

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.

Abbreviations used in this paper: Apc, adenomatous polyposis coli, bNF, β-napthoflavone, CPS I, carbamoylphosphate synthetase I, Dkk1, Dickkopf-1, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, GS, glutamine synthetase, Ihh, Indian hedgehog, LRP, low-density lipoprotein-related protein receptor, PEPCK, phosphoenolpyruvate carboxykinase, PFK, 6-phosphofructo-2-kinase, RT-PCR, reverse transcriptase polymerase chain reaction, Rrm2, ribonucleotide reductase