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Intestinal failure-associated liver disease model: a reduced phytosterol intravenous lipid emulsion prevents liver injury

Pediatric Research volume 97, pages 2454–2461 (2025)Cite this article

Abstract

Background

Long-term parenteral nutrition in children often results in intestinal failure-associated liver disease (IFALD). Phytosterols are plant steroids in vegetable oil-based intravenous lipid emulsions (ILEs) that are associated with IFALD. We investigated whether a phytosterol-depleted soybean oil ILE, compared to standard soybean oil ILE, prevented hepatotoxicity in a murine IFALD model.

Methods

Eight-week-old male C57BL/6 J mice were provided a fat-free high carbohydrate liquid diet for 19 days. Mice were intravenously administered ILEs as the sole fat source: Intralipid® (commercially available soybean oil ILE), Omegaven® (commercially available fish oil ILE), a low phytosterol soybean oil ILE (L-SOLE) or a high phytosterol soybean oil ILE (H-SOLE) with matched alpha tocopherol content. On days 6, 12, and 18 mice were administered escalating intraperitoneal doses of lipopolysaccharide.

Results

Compared to chow controls, mice that received Intralipid® demonstrated elevated plasma biomarkers of liver injury and histologic liver disease (hepatosteatosis, histologic inflammation, F4/80 staining). L-SOLE prevented both biochemical and histologic liver injury. Administration of H-SOLE also prevented biochemical liver injury, but not steatosis.

Conclusion

The combination of phytosterol removal and alpha tocopherol supplementation may reduce the toxicity associated with parenteral use of soybean oil-based ILE. Low phytosterol soybean oil may be a valuable component in safer next generation ILEs.

Impact

  • Half of children receiving long-term parenteral nutrition develop intestinal failure-associated liver disease (IFALD).

  • Standard intravenous lipid emulsions (ILEs) in parenteral nutrition are vegetable oil based and high in phytosterols (plant steroids); no low phytosterol vegetable oil-based ILE is available.

  • Phytosterols in ILEs are associated with IFALD.

  • In this study, a new phytosterol-depleted soybean oil was utilized in a laboratory-generated ILE. Use of the phytosterol-depleted soybean oil ILE prevented liver injury in a murine model of IFALD.

  • Phytosterol-depleted soybean oil may be utilized as a component of less toxic next-generation ILEs.

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Fig. 1: Study design, body weight, and normalized organ weights.
Fig. 2: Biochemical assessment of liver injury.
Fig. 3: Representative liver histology and pathologist scoring of steatosis.
Fig. 4: Evaluation of liver macrophage recruitment and inflammatory signaling.

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Data availability

All data generated or analyzed during this study are included in this published article as a supplementary file.

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Acknowledgements

This study received funding from Lipoid GmbH under a sponsored research agreement, National Institutes of Health grants 5T32HL007734 (SCF, TIH) and 2T32DK007754-22 (STT), the Beth Israel Deaconess Medical Center Richard and Sandra Cummings Research Fellowship (SCF), the Boston Children’s Hospital Vascular Biology Program, the Boston Children’s Hospital Surgical Foundation, the Hannah Lillie Fund, The Maisie Ellis & Friends Fund, and the Luke Raymond Celaya Research Fund. GmbH did not design the study, participate in the collection, analysis, or interpretation of data, and did not contribute to the writing of the manuscript.

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Authors and Affiliations

  1. Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, MA, USA

    Scott C. Fligor, Thomas I. Hirsch, Savas T. Tsikis, Amy Pan, Mikayla Quigley & Mark Puder

  2. Harvard Medical School, Boston, MA, USA

    Scott C. Fligor, Thomas I. Hirsch, Savas T. Tsikis, Kathleen M. Gura & Mark Puder

  3. Department of Pharmacy and the Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA, USA

    Kathleen M. Gura

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  1. Scott C. Fligor
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Contributions

SF, KG, and MP designed the study. SF, TH, ST, AP, and MQ acquired the data. SF analyzed the data. SF, TH, ST, and MP interpreted the data. The original draft was written by SF. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Mark Puder.

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Competing interests

A patent application has been filed by SF, KG, and MP entitled “Methods and Compositions Relation to Treatment and Prevention of Fatty Acid Deficiencies.”

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Fligor, S.C., Hirsch, T.I., Tsikis, S.T. et al. Intestinal failure-associated liver disease model: a reduced phytosterol intravenous lipid emulsion prevents liver injury. Pediatr Res 97, 2454–2461 (2025). https://doi.org/10.1038/s41390-024-03753-9

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