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Nat Commun. 2018 Apr 11;9(1):1393. doi: 10.1038/s41467-018-03764-1.

Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis.

Author information

1
Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, 80045, USA. Karim.Elkasmi@ucdenver.edu.
2
Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA. Karim.Elkasmi@ucdenver.edu.
3
Department of Immunology and Respiratory, Boehringer-Ingelheim Pharma GmbH &Co. KG, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany. Karim.Elkasmi@ucdenver.edu.
4
Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
5
Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA.
6
Department of Pediatrics, Providence Pediatric Gastroenterology, University of Washington, Anchorage, AK, 99515, USA.
7
Laboratory for Gastroenterology and Hepatology (GAEN), IREC, Universite Catholique de Louvain, Belgium 1, Place de l'Université, 1348, Louvain-la-Neuve, Belgium.
8
Cardiovascular Pulmonary Research and Division of Pediatric Critical Care, Department of Pediatrics, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
9
Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
10
Department of Pathology, University of Colorado School of Medicine, Building RC-1, North Tower, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
11
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, 12801, E 17th Ave, Aurora, CO, 80045, USA.
12
Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, 80045, USA. Ronald.Sokol@childrenscolorado.org.
13
Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA. Ronald.Sokol@childrenscolorado.org.

Abstract

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-1β 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-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB 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-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.

PMID:
29643332
PMCID:
PMC5895696
DOI:
10.1038/s41467-018-03764-1
[Indexed for MEDLINE]
Free PMC Article

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