Wnt-β-catenin in hepatobiliary homeostasis, injury, and repair

Abstract

Wnt-β-catenin signaling has emerged as an important regulatory pathway in the liver, playing key roles in zonation and mediating contextual hepatobiliary repair after injuries. In this review, we will address the major advances in understanding the role of Wnt signaling in hepatic zonation, regeneration, and cholestasis-induced injury. We will also touch on some important unanswered questions and discuss the relevance of modulating the pathway to provide therapies for complex liver pathologies that remain a continued unmet clinical need.

Design principles and therapeutic applications of novel synthetic WNT signaling agonists

“…Pathway inactivation by liver-specific deletion of receptors, ligands, or β-catenin abolishes pericentral gene expression signatures. 44 Pathway overactivation leads to expansion of the pericentral gene profile across the liver lobule. 45 , 46 In addition to its role in patterning the adult liver lobule, WNT/β-catenin activity acts as a critical instructive signal for hepatocyte proliferation and regeneration, inducing the expression of key cell-cycle regulators such as cyclin D1.…”

“… 45 , 46 In addition to its role in patterning the adult liver lobule, WNT/β-catenin activity acts as a critical instructive signal for hepatocyte proliferation and regeneration, inducing the expression of key cell-cycle regulators such as cyclin D1. 44 , 47 , 48 , 49 Genetic pathway inactivation in hepatocytes decreases liver size in mice and significantly delays hepatocyte proliferation and liver regeneration after partial hepatectomy (PH). 44 Conditional deletion of Apc , in contrast, causes hepatocyte hyperproliferation and increased liver size.…”

“… 44 , 47 , 48 , 49 Genetic pathway inactivation in hepatocytes decreases liver size in mice and significantly delays hepatocyte proliferation and liver regeneration after partial hepatectomy (PH). 44 Conditional deletion of Apc , in contrast, causes hepatocyte hyperproliferation and increased liver size. 45 Hence, given the crucial roles of WNT and RSPO in liver regeneration and metabolic zonation, stimulating WNT/β-catenin activity to treat various liver diseases has great therapeutic promise.…”