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Updated: Jun 29, 2025
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Parenteral nutrition emulsion inhibits CYP3A4 in an iPSC derived liver organoids testing platform
Sean P Harrison1, Saphira F Baumgarten1,2,3, Maria E Chollet3,4
1Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
Insights
Induced pluripotent stem cell-derived liver organoids model PN-associated liver disease (PNALD) in premature infants. These organoids show lipid accumulation and reduced CYP3A4 activity, indicating potential for testing new parenteral nutrition (PN) solutions.
Area of Science:
- Hepatology
- Stem Cell Biology
- Neonatology
Background:
- Parenteral nutrition (PN) is crucial for patients with intestinal failure, but premature newborns are at high risk for PN-associated liver disease (PNALD).
- PNALD manifests as steatosis, cholestasis, and gallbladder issues, necessitating predictive models for optimized nutrition.
- Current models lack the capacity to accurately predict PNALD development in vulnerable infant populations.
Purpose of the Study:
- To develop and validate a novel in vitro model for predicting PNALD using liver organoids.
- To assess the utility of induced pluripotent stem cell-derived liver organoids as a platform for PNALD research.
- To investigate the effects of different lipid emulsions used in PN on liver organoid function and viability.
Main Methods:
- Utilized induced pluripotent stem cell-derived liver organoids, mimicking early postnatal liver development.
- Exposed organoids to clinoleic or intralipid lipid emulsions for 7 days to simulate PN treatment.
- Analyzed lipid accumulation, hepatocyte gene expression, and enzyme activity (CYP3A4) in response to PN exposure.
Main Results:
- PN treatments led to significant lipid accumulation in hepatocytes within the organoids.
- A dose-dependent decrease in CYP3A4 activity and expression of key hepatocyte genes was observed.
- Organoid viability was not compromised by lipid emulsions, and high glucose levels did not influence the observed PNALD markers.
Conclusions:
- Liver organoids serve as a promising screening platform for developing less hepatotoxic PN solutions.
- Both tested lipid emulsions induced PNALD hallmarks, including lipid accumulation and reduced CYP3A4/CYP1A2 activity.
- Clinoleic at high doses upregulated inflammatory markers (IL-6, TLR4), suggesting differential hepatotoxicity.
Objectives:
Parenteral nutrition (PN) is used for patients of varying ages with intestinal failure to supplement calories. Premature newborns with low birth weight are at a high risk for developing PN associated liver disease (PNALD) including steatosis, cholestasis, and gallbladder sludge/stones. To optimize nutrition regimens, models are required to predict PNALD.
Methods:
We have exploited induced pluripotent stem cell derived liver organoids to provide a testing platform for PNALD. Liver organoids mimic the developing liver and contain the different hepatic cell types. The organoids have an early postnatal maturity making them a suitable model for premature newborns. To mimic PN treatment we used medium supplemented with either clinoleic (80% olive oil/20% soybean oil) or intralipid (100% soybean oil) for 7 days.
Results:
Homogenous HNF4a staining was found in all organoids and PN treatments caused accumulation of lipids in hepatocytes. Organoids exhibited a dose dependent decrease in CYP3A4 activity and expression of hepatocyte functional genes. The lipid emulsions did not affect overall organoid viability and glucose levels had no contributory effect to the observed results.
Conclusions:
Liver organoids could be utilized as a potential screening platform for the development of new, less hepatotoxic PN solutions. Both lipid treatments caused hepatic lipid accumulation, a significant decrease in CYP3A4 activity and a decrease in the RNA levels of both CYP3A4 and CYP1A2 in a dose dependent manner. The presence of high glucose had no additive effect, while Clinoleic at high dose, caused significant upregulation of interleukin 6 and TLR4 expression.
