Stat3 role in the protective effect of FXR Agonist in parenteral nutrition-associated cholestasis

Background and Aims: Parenteral nutrition (PN) in patients with intestinal failure can lead to cholestasis (PNAC). In a PNAC mouse model, farnesoid X receptor (FXR) agonist (GW4064) treatment alleviated IL-1 beta-dependent cholestatic liver injury. The objective of this study was to determine whether this hepatic protection of FXR activation is mediated through IL-6-STAT3 signaling. Approach and Results: Hepatic apoptotic pathways [Fas-associated protein with death domain (Fas) mRNA, caspase 8 protein, and cleaved caspase 3] and IL-6-STAT3 signaling, and expression of its downstream effectors Socs1/3 were all upregulated in the mouse PNAC model (dextran sulfate sodium enterally x 4d followed by total PN for 14 d). Il1r(-/-) mice were protected from PNAC in conjunction with suppression of the FAS pathway. GW4064 treatment in the PNAC mouse increased hepatic FXR binding to the Stat3 promoter, further increased STAT3 phosphorylation and upregulated Socs1 and Socs3 mRNA, and prevented cholestasis. In HepG2 cells and primary mouse hepatocytes, IL-1 beta induced IL-6 mRNA and protein, which were suppressed by GW4064. In IL-1 beta or phytosterols treated HepG2 and Huh7 cells, siRNA knockdown of STAT3 significantly reduced GW4064-upregulated transcription of hepatoprotective nuclear receptor subfamily 0, group B, member 2 (NR0B2) and ABCG8. Conclusions: STAT3 signaling mediated in part the protective effects of GW4064 in the PNAC mouse, and in HepG2 cells and hepatocytes exposed to either IL-1 beta or phytosterols, 2 factors critical in PNAC pathogenesis. These data demonstrate that FXR agonists may mediate hepatoprotective effects in cholestasis by inducing STAT3 signaling.