ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation

Cell Stem Cell. 2021 Oct 7;28(10):1822-1837.e10. doi: 10.1016/j.stem.2021.05.013. Epub 2021 Jun 14.


AXIN2 and LGR5 mark intestinal stem cells (ISCs) that require WNT/β-Catenin signaling for constant homeostatic proliferation. In contrast, AXIN2/LGR5+ pericentral hepatocytes show low proliferation rates despite a WNT/β-Catenin activity gradient required for metabolic liver zonation. The mechanisms restricting proliferation in AXIN2+ hepatocytes and metabolic gene expression in AXIN2+ ISCs remained elusive. We now show that restricted chromatin accessibility in ISCs prevents the expression of β-Catenin-regulated metabolic enzymes, whereas fine-tuning of WNT/β-Catenin activity by ZNRF3 and RNF43 restricts proliferation in chromatin-permissive AXIN2+ hepatocytes, while preserving metabolic function. ZNRF3 deletion promotes hepatocyte proliferation, which in turn becomes limited by RNF43 upregulation. Concomitant deletion of RNF43 in ZNRF3 mutant mice results in metabolic reprogramming of periportal hepatocytes and induces clonal expansion in a subset of hepatocytes, ultimately promoting liver tumors. Together, ZNRF3 and RNF43 cooperate to safeguard liver homeostasis by spatially and temporally restricting WNT/β-Catenin activity, balancing metabolic function and hepatocyte proliferation.

Keywords: AXIN2+ hepatocytes; LGR5; R-Spondin; WNT signaling; hepatocellular carcinoma; instestinal stem cells; liver regeneration; liver zonation; metabolism; spatial transcriptomics.

MeSH terms

  • Animals
  • Cell Proliferation
  • Hepatocytes / metabolism
  • Liver* / growth & development
  • Liver* / metabolism
  • Mice
  • Stem Cells / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / metabolism


  • beta Catenin
  • RNF43 protein, mouse
  • Ubiquitin-Protein Ligases
  • Znrf3 protein, mouse