Trends in Molecular Medicine
OpinionA Novel Perspective on the Biology of Bilirubin in Health and Disease
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
References (74)
Bilirubin inhibits the TNF alpha-related induction of three endothelial adhesion molecules
Biochem. Biophys. Res. Commun.
(2009)A bilirubin-inducible fluorescent protein from eel muscle
Cell
(2013)Metabolism of bilirubin by human cytochrome P450 2A6
Toxicol. Appl. Pharmacol.
(2012)Mitochondrial targeting of bilirubin regulatory enzymes: an adaptive response to oxidative stress
Toxicol. Appl. Pharmacol.
(2015)The role of Ah receptor in induction of human UDP-glucuronosyltransferase 1A1
Methods Enzymol.
(2005)Biliverdin reductase, a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1
J. Biol. Chem.
(2004)The human biliverdin reductase-based peptide fragments and biliverdin regulate protein kinase Cdelta activity: the peptides are inhibitors or substrate for the protein kinase C
J. Biol. Chem.
(2012)- et al.
Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease
Atherosclerosis
(2000) The molecular basis for the immunomodulatory activities of unconjugated bilirubin
Int. J. Biochem. Cell Biol.
(2013)Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert's syndrome?
Atherosclerosis
(2015)
Translational significance of heme oxygenase in obesity and metabolic syndrome
Trends Pharmacol. Sci.
The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it's time for reconciliation
Neurobiol. Dis.
Decreased activity of the antioxidant heme oxygenase enzyme: implications in ischemia and in Alzheimer's disease
Free Radic. Biol. Med.
Heme oxygenase-1 protects brain from acute excitotoxicity
Neuroscience
Heme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia
Neuroscience
Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation
J. Biol. Chem.
Acute iron overload and oxidative stress in brain
Toxicology
Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies
Exp. Biol. Med.
Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999-2004
Am. J. Med.
Bilirubin and glutathione have complementary antioxidant and cytoprotective roles
Proc. Natl. Acad. Sci. U.S.A.
Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis
J. Immunol.
Bilirubin promotes de novo generation of T regulatory cells
Cell Transplant.
Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase
Am. J. Physiol. Gastrointest. Liver Physiol.
Bilirubin - a natural inhibitor of vascular smooth muscle cell proliferation
Circulation
Bilirubin inhibits tumor cell growth via activation of ERK
Cell Cycle
Neural roles for heme oxygenase: contrasts to nitric oxide synthase
Proc. Natl. Acad. Sci. U.S.A.
Heme biosynthesis modulation via delta-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension
Am. J. Physiol. Lung Cell. Mol. Physiol.
Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications
Physiol. Rev.
Hemin decreases cardiac oxidative stress and fibrosis in a rat model of systemic hypertension via PI3K/Akt signalling
Cardiovasc. Res.
Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats
Endocrinology
Continuous de novo biosynthesis of haem and its rapid turnover to bilirubin are necessary for cytoprotection against cell damage
Sci. Rep.
Adaptive evolution of eel fluorescent proteins from fatty acid binding proteins produces bright fluorescence in the marine environment
PLoS ONE
The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth
Carcinogenesis
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
J. Clin. Invest.
Introducing the ‘TCDD-inducible AhR-Nrf2 gene battery’
Toxicol. Sci.
Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation
Proc. Natl. Acad. Sci. U.S.A.
The roles of aryl hydrocarbon receptor in immune responses
Int. Immunol.
Cited by (0)
- ‡
These authors contributed equally to this article.