Trends in Molecular Medicine
Volume 22, Issue 9, September 2016, Pages 758-768
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Opinion
A Novel Perspective on the Biology of Bilirubin in Health and Disease

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Historically known for its toxicity but recently recognized as a powerful protective molecule, BLB is gaining more attention due to its pleiotropic biomolecular effects and those of the enzymes involved in BLB metabolism (the ‘Yellow Players’).

Both heme oxygenase (HMOX) and biliverdin reductase (BLVR) (the main enzymes in BLB metabolism) act on numerous signaling pathways, with unsuspected biological consequences. The interconnections of such pathways highlight an incredibly complex biomolecular network. Yellow player molecules can have important physiological and pathological biological outcomes. Their still unexplored roles merit attention, offering the possibility of being targeted for therapeutic benefit.

The moderately high levels of UCB in the blood of patients with Gilbert syndrome are suggestive of the protective role of BLB in non-neurological pathologies (cardiovascular diseases, cancer, and metabolic syndrome).

Cells and tissues might actively maintain the intracellular homeostasis of BLB, with the yellow players being viewed as novel antioxidant mechanisms in a cell.

This new point of view might also be applicable to neurological diseases, where BLB levels are lower than in healthy subjects.

Unconjugated bilirubin (UCB) is known to be one of the most potent endogenous antioxidant substances. While hyperbilirubinemia has long been recognized as an ominous sign of liver dysfunction, recent data strongly indicate that mildly elevated bilirubin (BLB) levels can be protective against an array of diseases associated with increased oxidative stress. These clinical observations are supported by new discoveries relating to the role of BLB in immunosuppression and inhibition of protein phosphorylation, resulting in the modulation of intracellular signaling pathways in vascular biology and cancer, among others. Collectively, the evidence suggests that targeting BLB metabolism could be considered a potential therapeutic approach to ameliorate a variety of conditions.

Section snippets

From a Biological Waste Product to a Potent Biological Compound

UCB (see Glossary), the end product of the heme catabolic pathway, has long been recognized as a sign of liver dysfunction or a potential toxic factor causing severe brain damage in newborns. Mildly elevated BLB levels, as seen in patients with Gilbert syndrome, have been shown to be protective against an array of diseases associated with increased oxidative stress, such as cardiovascular diseases (CVD), diabetes and cancer 1, 2. These clinical observations are consistent with recent

A New Perspective on the Bilirubin–Biliverdin Antioxidant Cellular Cycle

Until recently, intracellular BLB was mainly considered to either derive from the blood or be regenerated from BLV via the BLV/BLB cycle [10]. The cycle is initiated by the microsomal HMOX1/2 (HMOX1 is inducible, whereas HMOX2 is constitutive) originating from BLV, and continued by the cytosolic BLV reductases (BLVRA and BLVRB) (Figure 1). The BLB antioxidant system involves de novo synthesis of heme mediated by the rate-limiting enzyme 5-aminolevulinic acid (ALA) synthase. The beneficial

Bilirubin in Cardiovascular Disease, Inflammatory Metabolic Syndrome, and Diabetes

In humans, a low (<7 μmol/l) total BLB concentration has been shown to be a risk factor for systemic diseases associated with increased oxidative stress, such as cardiovascular diseases (CVD), diabetes, metabolic syndrome, certain cancers, and autoimmune and neuropsychiatric diseases (reviewed in [38]). A meta-analysis study performed on a large male population with CVD showed that each micromolar decrease in serum BLB significantly increased the risk of atherosclerotic diseases [1], with a BLB

Bilirubin in Neurological Diseases

Clinical evidence indicates that lower serum BLB levels occur in a range of neurological diseases, such as Alzheimer disease (AD), dementia, multiple sclerosis, and cerebral infarctions (Table S1 in the supplemental information online). As described in AD, this may be mainly related to impairment in BLB production in the brain, rather than reduced supply from the blood to the brain, as has been described for other neurological diseases (see below).

Oxidative imbalance is a common feature of

Concluding Remarks

Here, we present several lines of evidence to support the notion that BLB and all the machinery involved in its production and metabolism (the yellow players) are deeply involved in several crucial steps of cellular pathways and homeostasis. As shown in Figure 2, this occurs by a complex, intricate network involving several genes and pathways, indicating that BLB and related enzymes have more important functions than merely representing waste products, as had been described during the 1980s.

Acknowledgments

This review is dedicated to all our colleagues involved at different levels in BLB research. In particular, we would like to thank the late J. Donald Ostrow, one of the founders of modern BLB research. S.G. and C.T. were supported by an in-house research grant from the Italian Liver Foundation. S.S. was supported by an in-house research grant from Children's Mercy Hospital of Kansas City. L.V. was supported by grants RVO-VFN64165/2013 from the Czech Ministry of Health and PRVOUK-P25/LF1/2 from

Glossary

Aryl hydrocarbon receptor (AhR)
ligand-activated transcription factor acting on aryl hydrocarbon response element (AHRE), xenobiotic response element (XRE), and drug response element (DRE) consensus regulatory sequences in the promoters of HMOX1, CYP1A1/2, CYP2A6, UGT1A1, SLCO1B1 (encoding OATP2), and ABCs, which are involved in bile pigment metabolism and transport.
Bilirubin/biliverdin redox cycle
BLB may be converted back to BLV via its oxidation by reactive oxygen species present during

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