Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-a (BVRA) and suppression of ugt1a1

Terry D. Hinds; Justin F. Creeden; Darren M. Gordon; Adam C. Spegele; Steven L. Britton; Lauren G. Koch; David E. Stec

doi:10.3390/antiox9090889

Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-a (BVRA) and suppression of ugt1a1

Terry D. Hinds, Justin F. Creeden, Darren M. Gordon, Adam C. Spegele, Steven L. Britton, Lauren G. Koch, David E. Stec

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

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.

Original language	English
Article number	889
Pages (from-to)	1-13
Number of pages	13
Journal	Antioxidants
Volume	9
Issue number	9
DOIs	https://doi.org/10.3390/antiox9090889
State	Published - Sep 2020

Bibliographical note

Funding Information:
Funding: 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.

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. Acknowledgments: The authors gratefully acknowledge Roy Schneider at the University of Toledo College of Medicine for the illustration in the illustration used as graphical abstract, Samantha McKee and Mariah Dupree in the Department of Physiology & Pharmacology at the University of Toledo College of Medicine for technician support with the treadmill running experiments and colony management of the LCR and HCR rats, and the Analytical and Assay Core Laboratory in the Department of Physiology & Biophysics at the University of Mississippi Medical Center.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

BVRA
Bilirubin
Exercise
Glycogen
HO-1
HO-2
Heme oxygenase
Mitochondria
Obesity
PPARalpha

ASJC Scopus subject areas

Biochemistry
Physiology
Molecular Biology
Clinical Biochemistry
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/antiox9090889

Cite this

@article{0fa44e6fdb674bc49ec9802eaaf30e2d,

title = "Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-a (BVRA) and suppression of ugt1a1",

abstract = "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.",

keywords = "BVRA, Bilirubin, Exercise, Glycogen, HO-1, HO-2, Heme oxygenase, Mitochondria, Obesity, PPARalpha",

author = "Hinds, {Terry D.} and Creeden, {Justin F.} and Gordon, {Darren M.} and Spegele, {Adam C.} and Britton, {Steven L.} and Koch, {Lauren G.} and Stec, {David E.}",

note = "Funding Information: Funding: 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. 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. Acknowledgments: The authors gratefully acknowledge Roy Schneider at the University of Toledo College of Medicine for the illustration in the illustration used as graphical abstract, Samantha McKee and Mariah Dupree in the Department of Physiology & Pharmacology at the University of Toledo College of Medicine for technician support with the treadmill running experiments and colony management of the LCR and HCR rats, and the Analytical and Assay Core Laboratory in the Department of Physiology & Biophysics at the University of Mississippi Medical Center. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = sep,

doi = "10.3390/antiox9090889",

language = "English",

volume = "9",

pages = "1--13",

number = "9",

}

TY - JOUR

T1 - Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-a (BVRA) and suppression of ugt1a1

AU - Hinds, Terry D.

AU - Creeden, Justin F.

AU - Gordon, Darren M.

AU - Spegele, Adam C.

AU - Britton, Steven L.

AU - Koch, Lauren G.

AU - Stec, David E.

N1 - Funding Information: Funding: 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. 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. Acknowledgments: The authors gratefully acknowledge Roy Schneider at the University of Toledo College of Medicine for the illustration in the illustration used as graphical abstract, Samantha McKee and Mariah Dupree in the Department of Physiology & Pharmacology at the University of Toledo College of Medicine for technician support with the treadmill running experiments and colony management of the LCR and HCR rats, and the Analytical and Assay Core Laboratory in the Department of Physiology & Biophysics at the University of Mississippi Medical Center. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

KW - BVRA

KW - Bilirubin

KW - Exercise

KW - Glycogen

KW - HO-1

KW - HO-2

KW - Heme oxygenase

KW - Mitochondria

KW - Obesity

KW - PPARalpha

UR - http://www.scopus.com/inward/record.url?scp=85091216595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85091216595&partnerID=8YFLogxK

U2 - 10.3390/antiox9090889

DO - 10.3390/antiox9090889

M3 - Article

AN - SCOPUS:85091216595

VL - 9

SP - 1

EP - 13

IS - 9

M1 - 889

ER -

Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-a (BVRA) and suppression of ugt1a1

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this