Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome proliferator-activated receptor-α (PPARα), a ligand-induced transcription factor, and the higher bilirubin HCR rats had significantly increased PPARα-target genes Fgf21, Abcd3, and Gys2. These are known to promote liver function and glycogen storage, which we found by Periodic acid–Schiff (PAS) staining that hepatic glycogen content was higher in the HCR versus the LCR. Our results demonstrate that exercise stimulates pathways that raise plasma bilirubin through alterations in hepatic enzymes involved in bilirubin synthesis and metabolism, improving liver function, and glycogen content. These mechanisms may explain the beneficial effects of exercise on plasma bilirubin levels and health in humans.

Document Type


Publication Date


Notes/Citation Information

Published in Antioxidants, v. 9, issue 9, 889.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)


Funding Information

This work was supported by the National Institutes of Health 1R01DK121797-01A1 (T.D.H.) and 1R01DK126884-01 (D.E.S.), the National Heart, Lung and Blood Institute K01HL-125445 (T.D.H.) and P01 HL05197-11 (D.E.S.), and the National Institute of General Medical Sciences P20GM104357-02 (D.E.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The LCR-HCR rat models are funded by the Office of Infrastructure Programs grant P40ODO21331 (to L.G.K and S.L.B) from the National Institutes of Health (USA). These rat models for low and high intrinsic exercise capacity are maintained as an international resource with support from the Department of Physiology and Pharmacology, The University of Toledo College of Medicine, Toledo, OH. Contact L.G.K (Lauren.Koch2@utoledo.edu) or S.L.B (brittons@umich.edu) for information on the rat models.