Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Abstract

Wnt/β-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of β-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. β-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive β-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, β-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of β-catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle is regulated by β-catenin-TCF complex. Thus β-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of β-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process, will be discussed. In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed.

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

“…Hepatocyte-specific deletion of ␤-catenin results in delayed hepatocyte proliferation in response to PH (61,66). Activated ␤-catenin translocates to nuclei and formation of ␤-catenin-T-cell factor/lymphoid enhancement factor complex influence target gene expression, i.e., cyclin D1, a key mediator of cell cycle progression at the G 1 phase of cell cycle (49). Key molecular mediators of upstream of ␤-catenin activation in regenerating livers are not well understood; however, both Wnt-dependent and Wnt-independent activation have been implicated (49).…”

Therapeutic Innovations for Targeting Hepatoblastoma

“…At the molecular level, Wnt signaling is quickly activated through inhibition of β-catenin degradation resulting in an increase of the protein by 2.5-fold and, therefore, its subsequent nuclear translocation (23). In the nucleus, β-catenin induces proliferation through the regulation of several genes such as CCND1 (20) and its protein level returns back to normal 48 hours post resection (23).…”

“…Particularly, this pathway is important in liver homeostasis: from embryonic liver to its functional maturation, which reinforces its role in hepatoblastoma tumorigenesis (18)(19)(20). In the adult liver, canonical Wnt signaling is only activated in the centrizonal region of the hepatic lobule as proven by positive nuclear and cytoplasmic β-catenin in this area (20,21). It is known to regulate genes involved in ammonia and xenobiotic metabolism (22).…”

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

“…1 Liver is a unique organ in its ability to respond physiologically through nonestem celledependent regeneration after surgical or toxin-induced loss of hepatic mass. 2 After partial hepatectomy (PH), several signaling pathways get activated in tandem to ensure proper initiation and progression of the regenerative process, which entails orderly proliferation of all resident cells of the liver.…”