Pharmacologic inhibition of HNF4α prevents parenteral nutrition associated cholestasis in mice

Prolonged parenteral nutrition (PN) can lead to PN associated cholestasis (PNAC). Intestinally derived lipopolysaccharides and infused PN phytosterols lead to activation of NFκB, a key factor in PNAC. Our objective was to determine if inhibition of HNF4α could interfere with NFκB to alleviate murine PNAC. We showed that HNF4α antagonist BI6015 (20 mg/kg/day) in DSS-PN (oral DSS x4d followed by Total PN x14d) mice prevented the increased AST, ALT, bilirubin and bile acids and reversed mRNA suppression of hepatocyte Abcg5/8, Abcb11, FXR, SHP and MRP2 that were present during PNAC. Further, NFκB phosphorylation in hepatocytes and its binding to LRH-1 and BSEP promoters in liver, which are upregulated in DSS-PN mice, were inhibited by BI6015 treatment. BI6015 also prevented the upregulation in liver macrophages of Adgre1 (F4/80) and Itgam (CD11B) that occurs in DSS-PN mice, with concomitant induction of anti-inflammatory genes (Klf2, Klf4, Clec7a1, Retnla). In conclusion, HNF4α antagonism attenuates PNAC by suppressing NFκB activation and signaling while inducing hepatocyte FXR and LRH-1 and their downstream bile and sterol transporters. These data identify HNF4α antagonism as a potential therapeutic target for prevention and treatment of PNAC.