Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma β-Hydroxybutyrate

Terry D. Hinds, Justin F. Creeden, Darren M. Gordon, Donald F. Stec, Matthew C. Donald, David E. Stec

Research output: Contribution to journalArticlepeer-review

30 Citations (SciVal)


The inverse relationship of plasma bilirubin levels with liver fat accumulation has prompted the possibility of bilirubin as a therapeutic for non-alcoholic fatty liver disease. Here, we used diet-induced obese mice with non-alcoholic fatty liver disease treated with pegylated bilirubin (bilirubin nanoparticles) or vehicle control to determine the impact on hepatic lipid accumulation. The bilirubin nanoparticles significantly reduced hepatic fat, triglyceride accumulation, de novo lipogenesis, and serum levels of liver dysfunction marker aspartate transaminase and ApoB100 containing very-low-density lipoprotein. The bilirubin nanoparticles improved liver function and activated the hepatic β-oxidation pathway by increasing PPARα and acyl-coenzyme A oxidase 1. The bilirubin nanoparticles also significantly elevated plasma levels of the ketone β-hydroxybutyrate and lowered liver fat accumulation. This study demonstrates that bilirubin nanoparticles induce hepatic fat utilization, raise plasma ketones, and reduce hepatic steatosis, opening new therapeutic avenues for NAFLD.

Original languageEnglish
Article number594574
JournalFrontiers in Pharmacology
StatePublished - Dec 18 2020

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health 1R01DK121797-01A1 (TH) and 1R01DK126884-01 (DS),

Funding Information:
We would like to thank John M. Rimoldi, Rama S. Gadepalli, and the Research Institute of Pharmaceutical Sciences at the University of Mississippi (Oxford, MS) for their synthesis of pegylated bilirubin used in the studies. The authors would also like to thank the Analytical and Assay Core Laboratory in the Department of Physiology and Biophysics at the University of Mississippi Medical Center.

Publisher Copyright:
© Copyright © 2020 Hinds, Creeden, Gordon, Stec, Donald and Stec.


  • HO-1
  • apolipoprotein
  • heme oxygenase
  • ketone
  • ketosis
  • non-alcoholic fatty liver disease
  • obesity

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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