Transcription dynamics in a physiological process: β-catenin signaling directs liver metabolic zonation

Abstract

The liver displays a remarkable phenomenon known as metabolic zonation. Highly specialized hepatocytes fulfill different metabolic functions that depend on their position along the porto-central axis, distinguishing "periportal" hepatocytes from "pericentral" hepatocytes. The mechanisms by which zonation is established have been extensively investigated since its initial discovery. Using murine models with β-catenin conditional activation or invalidation in the liver, a major role for the Wnt/β-catenin developmental pathway has been demonstrated in this functional heterogeneity of hepatocytes. Under physiological conditions, this pathway is activated in pericentral hepatocytes. This is partly due to the absence in the pericentral area of adenomatous polyposis coli, a negative regulator also known as the "zonation-keeper" of the liver lobule. The Wnt pathway induces a pericentral genetic program and represses a periportal genetic program in these hepatocytes. In mice with aberrant activation of β-catenin signaling, Wnt signaling also controls hepatocyte proliferation through a non-cell-autonomous mechanism. This pathway therefore controls metabolism and proliferation in liver cells, its role in proliferation being consistent with its involvement in liver cancer. Finally, the hepatic-enriched transcription factor Hnf4 has been shown to play a role in the Wnt-dependent transcription of zonated genes. From these findings, it now appears that the combinatorial interplay of different transcription factors with β-catenin supports liver metabolic zonation. We propose that genome-wide approaches using chromatin immunoprecipitation will allow to further explore the molecular determinants of β-catenin-dependent liver zonation.