Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

• Published in: Cell reports (Cambridge) 2019-12, Vol.29 (13), p.4553-4567.e7
• Main Authors: Kolbe, Erik, Aleithe, Susanne, Rennert, Christiane, Spormann, Luise, Ott, Fritzi, Meierhofer, David, Gajowski, Robert, Stöpel, Claus, Hoehme, Stefan, Kücken, Michael, Brusch, Lutz, Seifert, Michael, von Schoenfels, Witigo, Schafmayer, Clemens, Brosch, Mario, Hofmann, Ute, Damm, Georg, Seehofer, Daniel, Hampe, Jochen, Gebhardt, Rolf, Matz-Soja, Madlen
• Format: Article
• Language: English
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.104

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well. [Display omitted] •The Hh and Wnt pathways in healthy liver act largely complementary to each other•The Wnt/Hh module inversely controls spatiotemporal metabolic pathways in the liver•Inhibition of the Hh pathway leads to periportalization of the liver lobe•Liver-derived IHH seems to signal to other peripheral organs Wnt/β-catenin and Hh signaling contribute to embryogenesis as well as to the maintenance of organ homeostasis through intensive crosstalk. Here, Kolbe et al. describe that both pathways act largely complementary to each other in the healthy liver and that this crosstalk is responsible for the maintenance of metabolic zonation.