Prevention of Cholestatic Liver Disease Through BCL6-FXR Enterohepatic Crosstalk

Bile acid (BA) metabolism must be tightly regulated because BAs serve as metabolic signaling molecules but become cytotoxic at high levels. The farnesoid X receptor (FXR) is a crucial BA sensor, yet our understanding of its regulation and coordination with other transcription factors is limited. Here, we investigated the role of B-cell lymphoma 6 (BCL6) in regulating BA levels and how it coordinates with FXR to protect from BA overload.

We quantified cholesterol, BA levels, expression of key BA regulators, and hepatic damage markers in genetic mouse models with hepatic deletion of Bcl6 (Bcl6^LKO), global deletion of Fxr (Fxr^KO), or combined loss of both factors.

We identified an epigenomic link between BCL6- and FXR-regulated gene networks. BCL6 regulated BA homeostasis through multiple mechanisms, including suppression of BA synthesis, activation of fibroblast growth factor receptor 4 (FGFR4) expression to sensitize hepatocytes to FGF15-mediated repression of Cyp7a1, and induction of the BA reuptake transporter sodium taurocholate cotransporting polypeptide (NTCP). Combined loss of hepatic Bcl6 and whole body Fxr resulted in severe BA accumulation and hepatotoxicity, driven by a near-complete loss of hepatic small heterodimer partner (Shp), indicating that BCL6 and FXR co-repress BA synthesis and maintain BA homeostasis.

These findings identify BCL6 as a previously unrecognized integrator of FXR-mediated enterohepatic signaling and a critical regulator of BA metabolism, acting through both FXR-dependent and FXR-independent mechanisms to maintain BA homeostasis and protect the liver from BA-induced injury.