Role and Regulation of Wnt/β-Catenin in Hepatic Perivenous Zonation and Physiological Homeostasis

Abstract

Metabolic heterogeneity or functional zonation is a key characteristic of the liver that allows different metabolic pathways to be spatially regulated within the hepatic system and together contribute to whole body homeostasis. These metabolic pathways are segregated along the portocentral axis of the liver lobule into three hepatic zones: periportal, intermediate or midzonal, and perivenous. The liver performs complementary or opposing metabolic functions within different hepatic zones while synergistic functions are regulated by overlapping zones, thereby maintaining the overall physiological stability. The Wnt/β-catenin signaling pathway is well known for its role in liver growth, development, and regeneration. In addition, the Wnt/β-catenin pathway plays a fundamental and dominant role in hepatic zonation and signals to orchestrate various functions of liver metabolism and pathophysiology. The β-catenin protein is the central player in the Wnt/β-catenin signaling cascade, and its activation is crucial for metabolic patterning of the liver. However, dysregulation of Wnt/β-catenin signaling is also implicated in different liver pathologies, including those associated with metabolic syndrome. β-Catenin is preferentially localized in the central region of the hepatic lobule surrounding the central vein and regulates multiple functions of this region. This review outlines the role of Wnt/β-catenin signaling pathway in controlling the different metabolic processes surrounding the central vein and its relation to liver homeostasis and dysfunction.

Figure 1

Metabolic liver zonation, showing the different hepatic zones within the basic structural hepatic lobule and the functional responsibilities of the centrilobular hepatocytes in the perivenous zone. A: Overview of liver. B: The basic structural units of liver, called the hepatic lobules, organized into a honeycomb-like architecture. C: A single hexagon-like hepatic lobule with central vein located at the center and multiple portal triads at the periphery. D: Enlarged view of a single portal triad composed of a hepatic artery, a portal vein, and a bile duct. E: Outline of different perivenous zonal responsibilities in the liver. Figure was prepared using Biorender.com (Toronto, ON, Canada).

Figure 2

Wnt/β-catenin signaling and β-catenin activation for target gene transcription. A: Wnt off situation: In the absence of Wnt glycoprotein, β-catenin, a transcriptional co-activator and the effector molecule of the pathway, is bound in a destruction complex consisting of Axin, adenomatous polyposis coli, casein kinase 1 (CK-1), and glycogen synthase kinase-3β (GSK-3β). This destruction complex directs the phosphorylation and ubiquitination of β-catenin for its proteasomal degradation with the net result that β-catenin–mediated gene transcription is not activated. B: Wnt on situation (canonical Wnt/β-catenin signaling): When Wnt is present, it binds to the Frizzled receptor and coreceptor low-density lipoprotein receptor-related protein (LRP) 5/6. The Wnt-Frizzled-LRP complex causes dissociation of the destruction complex, which stabilizes β-catenin. The latter then translocates to the nucleus, where it binds to the transcription factors T-cell factor (TCF)/lymphocyte enhancer factor (LEF), resulting in transcription of Wnt target genes. Figure was prepared using Biorender.com (Toronto, ON, Canada).

Figure 3

Schematic representation for the role of Wnt/β-catenin signaling in regulating the different hepatic perivenous zonal functions and metabolic homeostasis. The Wnt proteins Wnt2 and Wnt9b, which are secreted by liver sinusoidal endothelial cells surrounding the central vein, bind to the hepatocyte cell membrane–associated receptor proteins. These Wnt proteins, via the canonical Wnt/β-catenin signaling pathway, mediate β-catenin nuclear translocation and consequent activation of Wnt target genes. The net result is the regulation of several physiological and metabolic functions of the hepatic perivenous zone by β-catenin. Figure was prepared using Biorender.com (Toronto, ON, Canada). CYP, cytochrome P450.