Maintenance of liver homeostasis relies on the metabolic function of this organ. To carry out these metabolic functions at a maximal possible efficiency, hepatocytes are both quiescent and highly specialized. They specialize as a function based on their position along the porto-central axis of the liver lobule that determines their fate as either “periportal” (PP), or “perivenous” (PV) hepatocytes. This zonation of function mainly affects ammonia detoxification, glucose/energy metabolism, and xenobiotic metabolism. Over the last 30 years, since the initial discovery of liver zonation, the mechanisms by which this zonation is established and maintained have been widely investigated. The Wnt/β(beta)-catenin developmental pathway has been recently shown to play a key role in this functional heterogeneity of mouse hepatocytes. It is activated in perivenous hepatocytes, partly due to the absence, in the perivenous area, of adenomatous polyposis coli (APC), a tumor suppressor gene product. APC is a negative regulator of Wnt signaling, also described as the “zonation-keeper” of the liver lobule. The Wnt pathway induces the PV genetic program and represses the PP genetic program. The ras/mapk/erk pathway acts in a reciprocal manner to counterbalance Wnt signaling and favors a PP genetic program. More recently, a cross-talk between the transcription factor Hnf4α(alpha) and Wnt signaling has been proposed as a potential mechanism of liver zonation.
KeywordsGenetic Program Adenomatous Polyposis Coli Liver Lobule Constitutive Androstane Receptor Hepatocyte Proliferation
We warmly thank Drs Jan Hengstler (IFADo, Dortmund, Germany), Stefan Hoehme and Dirk Drasdo (INRIA, France) for providing their three-dimensional reconstruction of the liver lobule (Fig. 2.1a) . This work was supported by INSERM, CNRS and the “Ligue Nationale Contre le Cancer” (LNCC, Comité de Paris, équipe Labellisée 2008), the ANR-07-PHYSIO and the CANCERSYS European network.
- 17.Nusse R, Fuerer C, Ching W, et al. Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol. 2008;73:59–66.Google Scholar
- 61.Hoehme et al. Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration Proc Natl Acad Sci USA. 2010;107(23):10371–6.Google Scholar