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.

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

“…We had previously shown that mice with the Gilbert's mutation UGT1A1*28 and hyperbilirubinemia were resistant to high-fat diet-induced hepatic steatosis by inhibiting de novo lipogenesis and activation of β-oxidation (Hinds et al, 2017). We have also shown that exercise elevated plasma bilirubin by suppressing hepatic UGT1A1 and increasing biliverdin reductase-A (BVRA) (Hinds et al, 2020), the enzyme that generates bilirubin (Adeosun et al, 2018;O'Brien et al, 2015), which improved hepatic glycogen storage and PPARα target genes (Hinds et al, 2020). Here, we found that PEG-BR reduced SCD1 and FAS while activating PPARα and ACOX1, improving hepatic steatosis in obese mice.…”

Identification of Binding Regions of Bilirubin in the Ligand-Binding Pocket of the Peroxisome Proliferator-Activated Receptor-A (PPARalpha)

“…These imply that possibly inducing heme oxygenase or BVRA might improve adiposity by increasing plasma bilirubin [ 35 ]. This concept is supported in a study showing that high-aerobic-capacity running rats had significantly higher plasma bilirubin and increased hepatic BVRA and PPARα than the low-running-capacity obese animals [ 36 ].…”

Serum Bilirubin Levels in Overweight and Obese Individuals: The Importance of Anti-Inflammatory and Antioxidant Responses

“…Indeed, intensive regular exercise, as seen in athletes, is correlated with elevated concentrations of total bilirubin [ 115 ]. Animal experiments showed that exercise stimulates pathways that raise serum bilirubin levels through alterations in the levels of hepatic enzymes; namely, increasing the expression of biliverdin reductase and consequently increasing bilirubin synthesis, as well as decreasing the expression of UGT1A1, which converts the biologically active unconjugated bilirubin into the non-active conjugated form [ 116 ].…”