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 bile acid sensor, but our understanding of its regulation and coordination with other transcription factors is limited. Here, we found that B cell lymphoma 6 (Bcl6) functions along with FXR to control bile acid levels. We found that mice lacking hepatic BCL6 (Bcl6LKO) had increased BA synthesis and serum levels. In line with this, Bcl6LKO mice had elevated serum cholesterol, the upstream substrate for BA synthesis, as well as reduced expression of the hepatic BA re-uptake transporter sodium-taurocholate cotransporting polypeptide (NTCP).  Furthermore, loss of BCL6 reduced hepatic fibroblast growth factor 4 (FGFR4) expression, causing dysregulated entero-hepatic BA feedback signaling. To better understand the relative contribution of BCL6 and FXR in regulating BA homeostasis, we generated mice with a combined deletion of hepatic BCL6 and FXR (Bcl6LKOFxrKO). Critically, combined deletion of FXR and hepatic BCL6 caused massive elevations in BA synthesis/levels compared to loss of Fxr or Bcl6 alone, which resulted in cholestatic liver damage. Mechanistically, we found that Bcl6LKO FxrKO mice had an almost complete loss of hepatic Shp expression, causing high levels of the rate-limiting BA synthesis enzyme CYP7A1. Together, these findings demonstrate that BCL6 and FXR function together to limit BA synthesis and protect the liver from cholestatic injury. Overall design: RNA-seq of liver from FXRKO and BCL6LKOFXRKO males