Publication Title
Nat Commun
Document Type
Article
Publication Date
4-11-2018
Keywords
ATP Binding Cassette Subfamily B Member 11/genetics; ATP Binding Cassette Subfamily B Member 11/immunology; ATP Binding Cassette Transporter, Sub-Family G, Member 5/genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 5/immunology; Animals; Caspase 1/genetics; Caspase 1/immunology; Caspases/genetics; Caspases/immunology; Cholestasis/etiology; Cholestasis/genetics; Cholestasis/immunology; Cholestasis/pathology; Disease Models, Animal; Gene Expression Regulation; Hepatocytes/immunology; Hepatocytes/pathology; Humans; Infant, Newborn; Interleukin-1beta/genetics; Interleukin-1beta/immunology; Lipoproteins/genetics; Lipoproteins/immunology; Liver/immunology; Liver/pathology; Liver X Receptors/genetics; Liver X Receptors/immunology; Macrophages/immunology; Macrophages/pathology; Male; Mice; Multidrug Resistance-Associated Proteins/genetics; Multidrug Resistance-Associated Proteins/immunology; NF-kappa B/genetics; NF-kappa B/immunology; Parenteral Nutrition/adverse effects; Receptors, CCR2/deficiency; Receptors, CCR2/genetics; Receptors, CCR2/immunology; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/immunology; Receptors, Interleukin-1/genetics; Receptors, Interleukin-1/immunology; Signal Transduction
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.
Clinical Institute
Digestive Health
Clinical Institute
Women & Children
Specialty/Research Institute
Gastroenterology
Specialty/Research Institute
Pediatrics
Specialty/Research Institute
Perinatology/Neonatology
