| First Author | El Kasmi KC | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1393 |
| PubMed ID | 29643332 | Mgi Jnum | J:265717 |
| Mgi Id | MGI:6157984 | Doi | 10.1038/s41467-018-03764-1 |
| Citation | El Kasmi KC, et al. (2018) Macrophage-derived IL-1beta/NF-kappaB signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 9(1):1393 |
| abstractText | In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1beta in PNAC. Pharmacological antagonism of IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1alpha and IL-1beta) prevents PNAC in mice. IL-1beta increases hepatocyte NF-kappaB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes (Abcc2, Abcb11, and Abcg5/8), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1beta, or NF-kappaB may be targets for restoring bile and sterol transport to treat PNAC. |
