Fig. 6.

Hypothetical model of PNAC pathogenesis. Increased intestinal permeability secondary to intestinal inflammation and dysbiosis promotes increased absorption of LPS into portal vein with subsequent TLR4-mediated activation²⁵ and caspase-1- dependent generation of IL-1β in recruited CCR2⁺ macrophages (phytosterols contribute to macrophage activation and IL-1β synthesis)²⁶. Through IL-1 receptor (IL-1R) binding on hepatocytes, IL-1β subsequently activates NF-κB in hepatocytes, which interferes with the ability of LXR and FXR to bind to promoters (red crosses) and activate expression of ABCG5/8, ABCB11, and ABCC2, resulting in decreased expression of BSEP, MRP2, and ABCG5/8 (blue downward arrows) and phytosterol retention (green dots). Retained phytosterols antagonize FXR activity leading to additional reduction in BSEP and MRP2 expression and subsequent retention of bile acids and bilirubin (additional phytosterol effects indicated by green downward arrows) and cholestasis. In addition, direct effects of LPS on the hepatocyte can suppress FXR activity (dotted line from LPS to hepatocyte)