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Review
. 2018 Oct;72(4):788-795.
doi: 10.1161/HYPERTENSIONAHA.118.11130.

Bilirubin, a Cardiometabolic Signaling Molecule

Terry D Hinds Jr  1 , David E Stec  2
Affiliations
Review

Bilirubin, a Cardiometabolic Signaling Molecule

Terry D Hinds Jr et al. Hypertension. 2018 Oct.

Erratum in

No abstract available

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Figures

Figure 1:
Figure 1:. Bilirubin as a Selective PPARα Modulator (SPPARM).
Bilirubin binds to the ligand-binding pocket of PPARα similar to other known activators WY-14,643 and fenofibrate. Also, bilirubin is also a potent antioxidant. Bilirubin has been shown to decrease the phosphorylation of serine 73 (Ser73) to increase transcription activity of PPARα , . The zinc finger (Z) DNA binding domains of PPARα bind at promoters of target genes. Bilirubin stimulates the promoter of several PPARα target genes including fibroblast growth factor 21 (Fgf21), carnitine palmitoyltransferase I (Cpt1), and cytochrome P450 4A (Cyp4A). WY 14,643 is stronger at inducing the cluster of differentiation 36 (Cd36) and to a lower extent glucose transporter 4 (Glut4) and Fgf21 promoters. Fenofibrate primary target is Cpt1. These genes play a specific role in anti-diabetic, anti-lipemic, anti-inflammatory, and anti-hypertensive actions of each compound.
Figure 2:
Figure 2:. Cardiovascular and Metabolic actions of Bilirubin.
In the heart, bilirubin lowers reactive oxygen species (ROS) and increases nitric oxide (NO) levels to improve coronary blood flow. Bilirubin may also act through PPARα to enhance fatty acid metabolism and afford cardioprotection. In blood vessels, bilirubin attenuates cholesterol deposition and immune cell infiltration to decrease plaque formation. In the liver, bilirubin and biliverdin reductase A (BVRA) phosphorylates AKT which inhibits glycogen synthase kinase 3β (GSK3β) preserving PPARα function to increase fibroblast growth factor 21 (Fgf21) and carnitine palmitoyltransferase I (Cpt1) for fat burning and protection against hepatic steatosis. In adipocytes, BVRA production of bilirubin activates PPARα to reduce lipid size. In the kidney, bilirubin improves glomerular filtration rate (GFR), renal blood flow (RBF), and nitric oxide synthase (NOS) levels while inhibiting ROS levels.
See this image and copyright information in PMC

References

    1. O’Brien L, Hosick PA, John K, Stec DE, Hinds TD Jr. Biliverdin reductase isozymes in metabolism. Trends Endocrinol. Metab 2015;26:212–220 - PMC - PubMed
    1. Weaver L, Hamoud AR, Stec DE, Hinds TD Jr. Biliverdin reductase and bilirubin in hepatic disease. Am J Physiol Gastrointest Liver Physiol 2018;314:G668–G676 - PMC - PubMed
    1. Hamoud AR, Weaver L, Stec DE, Hinds TD Jr. Bilirubin in the liver-gut signaling axis. Trends Endocrinol Metab 2018;29:140–150 - PMC - PubMed
    1. Sundararaghavan VL, Sindhwani P, Hinds TD Jr. Glucuronidation and ugt isozymes in bladder: New targets for the treatment of uroepithelial carcinomas? Oncotarget 2017;8:3640–3648 - PMC - PubMed
    1. Boon AC, Bulmer AC, Coombes JS, Fassett RG. Circulating bilirubin and defense against kidney disease and cardiovascular mortality: Mechanisms contributing to protection in clinical investigations. Am J Physiol Renal Physiol 2014;307:F123–136 - PubMed

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