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.
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This work was supported by the National Institutes of Health 1R01DK121797-01A1 (TH) and 1R01DK126884-01 (DS), the National Heart, Lung and Blood Institute K01HL-125445 (TH) and P01 HL05197-11 (DS), and the National Institute of General Medical Sciences P20GM104357-02 (DS). This project was partially supported by Grant Number P30GM122733 (Chemistry and DMPK Core Faculty)-funded by the National Institute of General Medical Sciences (NIGMS) a component of the National Institutes of Health (NIH) as one of its Centers of Biomedical Research Excellence (COBRE).
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Hinds, Terry D. Jr.; Creeden, Justin F.; Gordon, Darren M.; Stec, Donald F.; Donald, Matthew C.; and Stec, David E., "Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma β-Hydroxybutyrate" (2020). Pharmacology and Nutritional Sciences Faculty Publications. 111.