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

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. [Display omitted] •Intestinal stem cells (ISCs) and hepatocytes differentially use WNT signaling•WNT/β-Catenin activity correlates with proliferation of ISCs and hepatocytes•ZNRF3/RNF43 balance WNT signaling and their deletion promotes liver tumor formation•Inverse correlation between metabolism and proliferation in hepatocytes and ISCs How ISCs and hepatocytes differentially use WNT signaling is unclear. Sun et al. now reveal that ZNRF3/RNF43 balance WNT signaling in AXIN2+ hepatocytes to prevent proliferation while preserving metabolic zonation, and ZNRF3/RNF43 deletion promotes liver tumors. Restricted chromatin accessibility in ISCs prevents the expression of β-Catenin-regulated metabolic enzymes.