Wnt/β-Catenin Signaling as a Potential Target for the Treatment of Liver Cirrhosis Using Antifibrotic Drugs

Abstract

Cirrhosis is a form of liver fibrosis resulting from chronic hepatitis and caused by various liver diseases, including viral hepatitis, alcoholic liver damage, nonalcoholic steatohepatitis, and autoimmune liver disease. Cirrhosis leads to various complications, resulting in poor prognoses; therefore, it is important to develop novel antifibrotic therapies to counter liver cirrhosis. Wnt/β-catenin signaling is associated with the development of tissue fibrosis, making it a major therapeutic target for treating liver fibrosis. In this review, we present recent insights into the correlation between Wnt/β-catenin signaling and liver fibrosis and discuss the antifibrotic effects of the cAMP-response element binding protein/β-catenin inhibitor PRI-724.

Keywords: PRI-724; Wnt; liver fibrosis; β-catenin.

Figure 1

Process of hepatic stellate cell (HSC) activation and liver fibrosis progression. Damaged cells secrete damage-associated molecular patterns (DAMPs) and reactive oxygen species (ROS). These factors activate quiescent HSCs directly and indirectly through the action of Kupffer cells, T cells, neutrophils, and natural killer (NK) cells. Activated HSCs produce extracellular matrix (ECM) components and tissue inhibitors of metalloproteinases (TIMPs), which accelerates the deposition of ECM components and results in liver fibrosis progression. CCL2, C–C chemokine ligand 2; IL, interleukin; NASH, nonalcoholic steatohepatitis; SMA, smooth muscle actin; TNF, tumor necrosis factor.

Figure 2

In the presence of Wnt, Dishevelled (Dvl) prevents β-catenin phosphorylation by inhibiting glycogen synthase kinase 3β (GSK3β) activity. β-catenin is stabilized and migrates to the nucleus, where it binds to T cell factor (TCF). In the absence of Wnt signaling, β-catenin is phosphorylated by GSK3β and casein kinase 1α (CK1α) and subsequently ubiquitinated by β-transducin repeat containing protein (βTrCP). Finally, β-catenin is degraded by the proteasome.

Figure 3

The effects of CBP/β-catenin inhibitors. CBP/β-catenin inhibitors exert known effects on HSCs and immune cells, but their precise effects in hepatocytes are still unclear.

Figure 4

Histopathology of hepatic lobules stained with Sirius Red (400×). Liver biopsy sample from patient C2-03 (40 mg/m²/day PRI-724 in a CP class B cohort) at 12-weeks post-PRI-724 treatment. Scale bar = 50 μm.