Bile Acid Induced Inflammation and the Role of β-Catenin

Recent studies have suggested that a major mechanism of cholestatic liver injury is the induction of cytokines induced by increases in liver tissue bile acids.^1,2 The release of these cytokines into blood attracts neutrophils and T cells, resulting in liver inflammation and tissue injury. Bile acid homeostasis is regulated by the nuclear receptor, the farnesoid X receptor (FXR), which normally is bound in a complex with β-catenin in the cytosol. In the absence of β-catenin, or when it is reduced, FXR can translocate to the nucleus where it increases the transcription of Small heterodimer partner (SHP) resulting in the inhibition of Sodium taurocholate co-transporting polypeptide (NTCP), the major bile acid uptake transporter, stimulating bile acid efflux into blood via Organic solute transporter alpha and beta (OSTα–OSTβ) and inhibiting Cytochrome P450 7A1 (Cyp7a1), the rate-limiting step in bile acid synthesis from cholesterol. The net result is that bile acid–induced cholestatic liver injury is reduced.

β-catenin is a dual-function protein, involved in the regulation of cell–cell adhesion and gene transcription, where the latter is the main mechanism by which the Wingless-related integration site (Wnt) signaling pathway is affected. In the accompanying article, Ayers et al³ hypothesized that simultaneous suppression of β-catenin and activation of FXR should reduce liver injury in models of cholestatic liver injury produced by bile duct ligation in the mouse. To do so, they used a Wnt inhibitor, Wnt-C59, and several FXR agonists including obeticholic acid and tropifexor. Wnt signaling pathways are signal transduction pathways that transmit signals from surface receptors through the cell. The canonical Wnt pathway results in regulation of gene expression (via β-catenin), while the noncanonical Wnt pathway regulates calcium signaling, the cytoskeleton, and cell shape. After 12 days of treatment with the Wnt inhibitor, which acts on both pathways and in all cells, cholestatic liver injury and bile infarcts indeed were reduced. However, the striking findings were the absence of significant changes in bile acid levels and transporters and their RNA sequencing analysis, which indicated that cholangiocyte activation and nuclear factor-κB–dependent inflammation were suppressed, resulting in leaving cholangiocyte gene expression in a quiescent state. These findings are all the more remarkable given that previous publications by the same authors showed major reductions in hepatic levels of bile acids, Cyp7a1, and bile acid transporter expression when β-catenin was knocked out in the mouse.⁴ As explained by the authors, the difference in the 2 studies is that in the absence of β-catenin in the knockout mouse, FXR is untethered and free to transfer to the nucleus and inhibit bile acid flux, while in the current studies, β-catenin transcription activity is inhibited but the protein remains intact. However, in this study, it is the loss of Wnt proteins that regulate cholangiocyte proliferation and activation, which is primarily responsible for the protection from Bile duct ligation (BDL)-induced injury. Given that noncanonical Wnt pathways also can influence bile duct proliferation, much more analysis of Wnt’s pluripotential effects will be needed to fully understand this mechanism. Nevertheless, it should be emphasized that this novel effect of Wnt activity to reprogram reactive proinflammatory cholangiocytes (so characteristic of many cholangiopathies⁵) to a quiescent phenotype, opens up the possibility for therapeutic interventions and thus is a major contribution to the field of cholestatic liver injury.