FIG. 6.

Proposed role of LRH-1 in PNAC pathogenesis. Intestinal injury, dysbiosis, and hyperpermeability caused by intestinal failure promote LPS (and other pathogen-associated molecular patterns) absorption into portal vein, subsequently recruiting and activating liver macrophages to generate IL-1β, which binds to IL-1 receptor on hepatocytes. This triggers activation of NF-κB, which binds to promoter of NR5A2/LRH-1 to inhibit its expression, as well as FXR and LXR target genes. This results in suppression of downstream ABCG5/8 transcription and subsequent hepatocyte accumulation of phytosterols infused in the PN solution, which further antagonize FXR signaling and thus down-regulating canalicular ABCB11/BSEP and ABCC2/MRP2, promoting retention of bile acids and bilirubin and culminating in cholestatic injury. Retained PN phytosterols may also directly activate hepatic macrophages and magnify cytokine production. Abbreviation: FXRE, farnesoid X receptor response element.