To further elucidate the molecular and cellular mechanisms in the pathogenesis of PNAC, in the present study we combine genetic, molecular, and pharmacological approaches to demonstrate an essential role for macrophage-derived IL-1β as a key cytokine in PNAC, activating hepatocyte NF-κB, which in turn interferes with farnesoid X receptor (FXR) and liver X receptor (LXR) signaling to result in transcriptional suppression of bile and sterol transporters, culminating in cholestasis. This evidence concerns the gene NR1H4 and cholestasis.