Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease

Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component...

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Published inScience translational medicine Vol. 5; no. 206; p. 206ra137
Main Authors El Kasmi, Karim C, Anderson, Aimee L, Devereaux, Michael W, Vue, Padade M, Zhang, Wujuan, Setchell, Kenneth D R, Karpen, Saul J, Sokol, Ronald J
Format Journal Article
LanguageEnglish
Published United States 09.10.2013
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Abstract Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)-based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD.
AbstractList Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)-based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD.
Author Sokol, Ronald J
Anderson, Aimee L
Karpen, Saul J
Vue, Padade M
El Kasmi, Karim C
Devereaux, Michael W
Zhang, Wujuan
Setchell, Kenneth D R
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  surname: El Kasmi
  fullname: El Kasmi, Karim C
  organization: Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
– sequence: 2
  givenname: Aimee L
  surname: Anderson
  fullname: Anderson, Aimee L
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  surname: Devereaux
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  givenname: Padade M
  surname: Vue
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  givenname: Kenneth D R
  surname: Setchell
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/24107776$$D View this record in MEDLINE/PubMed
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Snippet Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with...
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StartPage 206ra137
SubjectTerms Animals
Bile - secretion
Bile Canaliculi - drug effects
Bile Canaliculi - metabolism
Bile Canaliculi - pathology
Bone Marrow Cells - drug effects
Bone Marrow Cells - metabolism
Bone Marrow Cells - pathology
Disease Models, Animal
Emulsions
Fish Oils - pharmacology
Gastrointestinal Tract - drug effects
Gastrointestinal Tract - microbiology
Gene Expression Regulation - drug effects
Kupffer Cells - drug effects
Kupffer Cells - metabolism
Kupffer Cells - pathology
Lipids - chemistry
Liver - metabolism
Liver - pathology
Liver Diseases - genetics
Liver Diseases - pathology
Liver Diseases - prevention & control
Macrophage Activation - drug effects
Membrane Transport Proteins - metabolism
Mice
Mice, Inbred C57BL
Microbiota - drug effects
Parenteral Nutrition - adverse effects
Phytosterols - toxicity
Signal Transduction
Solutions
Stigmasterol - blood
Toll-Like Receptor 4 - metabolism
Title Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease
URI https://www.ncbi.nlm.nih.gov/pubmed/24107776
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