Reactive Oxygen Species (ROS) and Antioxidants as Immunomodulators in Exercise: Implications for Heme Oxygenase and Bilirubin

Abstract

Exercise is commonly prescribed as a lifestyle treatment for chronic metabolic diseases as it functions as an insulin sensitizer, cardio-protectant, and essential lifestyle tool for effective weight maintenance. Exercise boosts the production of reactive oxygen species (ROS) and subsequent transient oxidative damage, which also upregulates counterbalancing endogenous antioxidants to protect from ROS-induced damage and inflammation. Exercise elevates heme oxygenase-1 (HO-1) and biliverdin reductase A (BVRA) expression as built-in protective mechanisms, which produce the most potent antioxidant, bilirubin. Together, these mitigate inflammation and adiposity. Moderately raising plasma bilirubin protects in two ways: (1) via its antioxidant capacity to reduce ROS and inflammation, and (2) its newly defined function as a hormone that activates the nuclear receptor transcription factor PPARα. It is now understood that increasing plasma bilirubin can also drive metabolic adaptions, which improve deleterious outcomes of weight gain and obesity, such as inflammation, type II diabetes, and cardiovascular diseases. The main objective of this review is to describe the function of bilirubin as an antioxidant and metabolic hormone and how the HO-1-BVRA-bilirubin-PPARα axis influences inflammation, metabolic function and interacts with exercise to improve outcomes of weight management.

Keywords: BVRA; HO-1; PPARα; bilirubin; biliverdin reductase; inflammation; metabolic disease; nitrate; nutraceuticals; vitamin D; vitamin E.

Figure 1

Overview of heme oxygenase and bilirubin interaction with exercise. Exercise increases reactive oxygen species (ROS) and potentiates oxidative DNA damage. The body compensates with oxidative stress by upregulating heme oxygenase-1 (HO-1), which generates the antioxidant bilirubin to help prevent excessive oxidative damage. Bilirubin also directly binds to the PPARα nuclear receptor to induce genes that suppress lipid accumulation and has cardiogenic and hepato-protective effects.

Figure 2

Relationship of HO-1 and ROS in habitually trained versus untrained subjects. Individuals who have performed a single bout of exercise (non-trained) versus individuals with exercise training experience (trained).

Figure 3

Redox Balance of ROS and Antioxidants. Exercise potentiates the release of reactive oxygen species due to increased oxidative exposure. However, exercise training also induces an adaptive response with the upregulation of antioxidant defense mechanisms that will help restore redox balance. The downregulation of endogenous antioxidant systems or the increased production of reactive oxygen species can precipitate an imbalance in redox balance and potentiate chronic oxidative damage.

Figure 4

The heme oxygenase pathway signaling during exercise. Exercising (aerobic) raises plasma bilirubin levels by (1) suppression of the glucuronyl transferase enzyme UGT1A1 that conjugates bilirubin for removal from blood, and (2) activation of the heme oxygenase pathway (HO-1-BVRA-PPARα). The increased bilirubin combats reactive oxygen species (ROS) and ROS-induced inflammation and DNA damage. The bilirubin also activates the nuclear receptor transcription factor, PPARα, to reduce adiposity. Created with BioRender.com (accessed on 9 December 2021).

Figure 5

Selectivity of bilirubin for the PPAR isoforms and signaling mechanisms. The PPAR isoforms are bound by corepressors proteins until they are bound to the ligand, which induces a change from co-repressors to co-activators. Unconjugated bilirubin enters the cells and activates PPARα and not the PPARγ or PPARβ/δ isoforms. Bilirubin binding to PPARα induces a complex with RXR causing an exchange of corepressor proteins for co-activators. The bilirubin-induced PPARα-RXR complex controls specific genes for metabolic control of adiposity (UCP1, CPT1A, FGF21, ADRB3, and others), which might be based upon specific co-activators (PGC1α, NCOA1, NCOA2, MED1, etc.) bound in the complex.

Figure 6

Model of how HO-1-bilirubin improves insulin sensitivity. Upregulation of HO-1-bilirubin is a multifactorial influencer of different metabolic processes such as induction phosphorylated Akt (Thr309), adiponectin production, and activation of PPARα-FGF21 pathways.