For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the "classical" hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various "diseases of civilization." Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.

4th Department of Internal Medicine and Institute of Medical Biochemistry and Laboratory Diagnostics General Faculty Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235(4792):1043-1046.

Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1-57.

Vítek L, Ostrow JD. Bilirubin chemistry and metabolism; harmful and protective aspects. Curr Pharm Des. 2009;15(25):2869-2883.

Wagner KH, Wallner M, Molzer C, et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin Sci (Lond). 2015;129(1):1-25.

Vítek L, Hubacek JA, Pajak A, et al. Association between plasma bilirubin and mortality. Ann Hepatol. 2019;18(2):379-385.

Vítek L. Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations? Arch Biochem Biophys. 2019;672:108062.

Gazzin S, Vítek L, Watchko J, Shapiro SM, Tiribelli C. A novel perspective on the biology of bilirubin in health and disease. Trends Mol Med. 2016;22(9):758-768.

Vítek L. Bile acids in the treatment of cardiometabolic diseases. Ann Hepatol. 2017;16(0):37-46.

Vítek L, Haluzik M. The role of bile acids in metabolic regulation. J Endocrinol. 2016;228(3):R85-R96.

Berk PD, Rodkey FL, Blaschke TF, Collison HA, Waggoner JG. Comparison of plasma bilirubin turnover and carbon monoxide production in man. J Lab Clin Med. 1974;83(1):29-37.

Levin W, Kuntzman R. Biphasic decrease of radioactive hemoprotein from liver microsomal CO-binding particles. Effect of 3-methylcholanthrene. J Biol Chem. 1969;244(13):3671-3676.

Levi AJ, Gatmaitan Z, Arias IM. Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions. J Clin Invest. 1969;48(11):2156-2167.

Arias IM. Liver function from Y to Z. J Clin Invest. 2012;122(8):2763-2764.

Takeda TA, Mu A, Tai TT, Kitajima S, Taketani S. Continuous de novo biosynthesis of haem and its rapid turnover to bilirubin are necessary for cytoprotection against cell damage. Sci Rep. 2015;5:10488.

Shen YF, Tsai MR, Chen SC, et al. Imaging endogenous bilirubins with two-photon fluorescence of bilirubin dimers. Anal Chem. 2015;87(15):7575-7582.

Vasavda C, Kothari R, Malla AP, et al. Bilirubin links heme metabolism to neuroprotection by scavenging superoxide. Cell Chem Biol. 2019;26(10):1450-1460.

Park JS, Nam E, Lee HK, Lim MH, Rhee HW. In cellulo mapping of subcellular localized bilirubin. ACS Chem Biol. 2016;11(8):2177-2185.

Gruber DF, Gaffney JP, Mehr S, et al. Adaptive evolution of eel fluorescent proteins from fatty acid binding proteins produces bright fluorescence in the marine environment. PLoS One. 2015;10(11):e0140972.

Funahashi A, Komatsu M, Furukawa T, et al. Eel green fluorescent protein is associated with resistance to oxidative stress. Comp Biochem Physiol C Toxicol Pharmacol. 2016;181-182:35-39.

Dennery PA. Signaling function of heme oxygenase proteins. Antioxid Redox Signal. 2014;20(11):1743-1753.

Maines MD. New insights into biliverdin reductase functions: linking heme metabolism to cell signaling. Physiology. 2005;20:382-389.

Lerner-Marmarosh N, Shen J, Torno MD, Kravets A, Hu Z, Maines MD. Human biliverdin reductase: a member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity. Proc Natl Acad Sci USA. 2005;102(20):7109-7114.

Kravets A, Hu Z, Miralem T, Torno MD, Maines MD. Biliverdin reductase, a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1. J Biol Chem. 2004;279(19):19916-19923.

Lerner-Marmarosh N, Miralem T, Gibbs PE, Maines MD. Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling. Proc Natl Acad Sci USA. 2008;105(19):6870-6875.

Phelan D, Winter GM, Rogers WJ, Lam JC, Denison MS. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys. 1998;357:155-163.

Dietrich C, Kaina B. The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth. Carcinogenesis. 2010;31(8):1319-1328.

Yueh MF, Bonzo JA, Tukey RH. The role of Ah receptor in induction of human UDP-glucuronosyltransferase 1A1. Methods Enzymol. 2005;400:75-91.

Yeager RL, Reisman SA, Aleksunes LM, Klaassen CD. Introducing the “TCDD-inducible AhR-Nrf2 gene battery”. Toxicol Sci. 2009;111(2):238-246.

Hansen TW, Mathiesen SB, Walaas SI. Bilirubin has widespread inhibitory effects on protein phosphorylation. Pediatr Res. 1996;39:1072-1077.

Nguyen NT, Hanieh H, Nakahama T, Kishimoto T. The roles of aryl hydrocarbon receptor in immune responses. Int Immunol. 2013;25(6):335-343.

Hahn ME. Aryl hydrocarbon receptors: diversity and evolution. Chem Biol Interact. 2002;141(1-2):131-160.

Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 2019;19(3):184-197.

Harper PA, Riddick DS, Okey AB. Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor. Biochem Pharmacol. 2006;72(3):267-279.

Yin J, Sheng B, Han B, et al. The AhR is involved in the regulation of LoVo cell proliferation through cell cycle-associated proteins. Cell Biol Int. 2016;40(5):560-568.

Koliopanos A, Kleeff J, Xiao Y, et al. Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer. Oncogene. 2002;21(39):6059-6070.

Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the US population: gender effect and inverse correlation with colorectal cancer. Hepatology. 2004;40(4):827-835.

Jiraskova A, Novotny J, Novotny L, et al. Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer. Int J Cancer. 2012;131(7):1549-1555.

Wheeler MA, Rothhammer V, Quintana FJ. Control of immune-mediated pathology via the aryl hydrocarbon receptor. J Biol Chem. 2017;292(30):12383-12389.

Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol. 2013;45(12):2843-2851.

Lenicek M, Duricova D, Hradsky O, et al. The relationship between serum bilirubin and Crohn's disease. Inflamm Bowel Dis. 2014;20(3):481-487.

Peng F, Deng X, Yu Y, et al. Serum bilirubin concentrations and multiple sclerosis. J Clin Neurosci. 2011;18(10):1355-1359.

Fischman D, Valluri A, Gorrepati VS, Murphy ME, Peters I, Cheriyath P. Bilirubin as a protective factor for rheumatoid arthritis: an NHANES study of 2003-2006 data. J Clin Med Res. 2010;2(6):256-260.

Vítek L, Muchova L, Jancova E, et al. Association of systemic lupus erythematosus with low serum bilirubin levels. Scand J Rheumatol. 2010;39(6):480-484.

Neavin DR, Liu D, Ray B, Weinshilboum RM. The role of the aryl hydrocarbon receptor (AHR) in immune and inflammatory diseases. Int J Mol Sci. 2018;19(12):3851.

Kim JB, Pjanic M, Nguyen T, et al. TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells. PLoS Genet. 2017;13(5):e1006750.

Pernomian L, da Silva CH. Current basis for discovery and development of aryl hydrocarbon receptor antagonists for experimental and therapeutic use in atherosclerosis. Eur J Pharmacol. 2015;764:118-123.

Longhi MS, Moss A, Jiang ZG, Robson SC. Purinergic signaling during intestinal inflammation. J Mol Med. 2017;95(9):915-925.

Bock KW. Human AHR functions in vascular tissue: pro- and anti-inflammatory responses of AHR agonists in atherosclerosis. Biochem Pharmacol. 2019;159:116-120.

Shinde R, McGaha TL. The aryl hydrocarbon receptor: connecting immunity to the microenvironment. Trends Immunol. 2018;39(12):1005-1020.

Zhang S, Qin C, Safe SH. Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect. 2003;111(16):1877-1882.

Ciolino HP, Daschner PJ, Yeh GC. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem J. 1999;340(pt 3):715-722.

Suk J, Jasprova J, Biedermann D, et al. Isolated silymarin flavonoids increase systemic and hepatic bilirubin concentrations and lower lipoperoxidation in mice. Oxid Med Cell Long 2019. 2019;2019:6026902.

Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids. 2007;72(3):231-246.

Yang H, Wang H. Signaling control of the constitutive androstane receptor (CAR). Protein Cell. 2014;5(2):113-123.

Ihunnah CA, Jiang M, Xie W. Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta. 2011;1812(8):956-963.

Huang W, Zhang J, Chua SS, et al. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA. 2003;100(7):4156-4161.

Kachaylo EM, Yarushkin AA, Pustylnyak VO. Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes. Eur J Pharmacol. 2012;679(1-3):139-143.

Roth A, Looser R, Kaufmann M, et al. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol Pharmacol. 2008;73(4):1282-1289.

Handschin C, Meyer UA. Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys. 2005;433(2):387-396.

Xu P, Zhai Y, Wang J. The role of PPAR and its cross-talk with CAR and LXR in obesity and atherosclerosis. Int J Mol Sci. 2018;19(4):1260.

Sberna AL, Assem M, Xiao R, et al. Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2011;31(10):2232-2239.

Dong B, Saha PK, Huang W, et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA. 2009;106(44):18831-18836.

Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as nuclear receptors for nutrient and energy metabolism. Molecules. 2019;24(14):2545.

Gordon DM, Blomquist TM, Miruzzi SA, McCullumsmith R, Stec DE, Hinds TD Jr. RNA sequencing in human HepG2 hepatocytes reveals PPAR-alpha mediates transcriptome responsiveness of bilirubin. Physiol Genomics. 2019;51(6):234-240.

Hinds TD Jr, Hosick PA, Chen S, et al. Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. Am J Physiol Endocrinol Metab. 2017;312(4):E244-E252.

Stec DE, John K, Trabbic CJ, et al. Bilirubin binding to PPARalpha inhibits lipid accumulation. PLoS One. 2016;11(4):e0153427.

Hinds TD Jr, Burns KA, Hosick PA, et al. Biliverdin reductase A attenuates hepatic steatosis by inhibition of glycogen synthase kinase (GSK) 3beta phosphorylation of serine 73 of peroxisome proliferator-activated receptor (PPAR) alpha. J Biol Chem. 2016;291:25179-25191.

Hinds TD Jr, Stec DE. Bilirubin, a cardiometabolic signaling molecule. Hypertension. 2018;72(4):788-795.

Hinds TD Jr, Sodhi K, Meadows C, et al. Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity. 2014;22(3):705-712.

Pepino MY, Kuda O, Samovski D, Abumrad NA. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu Rev Nutr. 2014;34:281-303.

Lee JH, Wada T, Febbraio M, et al. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology. 2010;139(2):653-663.

Andersson C, Weeke P, Fosbol EL, et al. Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial. Metabolism. 2009;58(8):1109-1115.

Liu J, Dong H, Zhang Y, et al. Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPARgamma levels. Sci Rep. 2015;5:9886.

Shao X, Wang M, Wei X, et al. Peroxisome proliferator-activated receptor-gamma: master regulator of adipogenesis and obesity. Curr Stem Cell Res Ther. 2016;11(3):282-289.

He G, Sung YM, Digiovanni J, Fischer SM. Thiazolidinediones inhibit insulin-like growth factor-I-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity. Cancer Res. 2006;66(3):1873-1878.

Wang L, Yin Y, Hou G, Kang J, Wang Q. Peroxisome proliferator-activated receptor (PPARgamma) plays a protective role in cigarette smoking-induced inflammation via AMP-activated protein kinase (AMPK) signaling. Med Sci Monit. 2018;24:5168-5177.

Molzer C, Wallner M, Kern C, et al. Features of an altered AMPK metabolic pathway in Gilbert's syndrome, and its role in metabolic health. Sci Rep. 2016;6:30051.

Shepherd RE, Moreno FJ, Cashore WJ, Fain JN. Effects of bilirubin on fat cell metabolism and lipolysis. Am J Physiol. 1979;237:E504-E508.

Dong H, Huang H, Yun X, et al. Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology. 2014;155(3):818-828.

Vítek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol. 2012;3:55.

Zhou X, Cao L, Jiang C, et al. PPARalpha-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis. Nat Commun. 2014;5:4573.

Storch J, Corsico B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr. 2008;28:73-95.

Hotamisligil GS, Bernlohr DA. Metabolic functions of FABPs-mechanisms and therapeutic implications. Nat Rev Endocrinol. 2015;11(10):592-605.

Liu QY, Quinet E, Nambi P. Adipocyte fatty acid-binding protein (aP2), a newly identified LXR target gene, is induced by LXR agonists in human THP-1 cells. Mol Cell Biochem. 2007;302(1-2):203-213.

Xu J, Lee ES, Baek SH, et al. Effect of bilirubin on triglyceride synthesis in streptozotocin-induced diabetic nephropathy. J Korean Med Sci. 2014;29(suppl 2):S155-S163.

Storch J, McDermott L. Structural and functional analysis of fatty acid-binding proteins. J Lipid Res. 2009;50(suppl):S126-S131.

Guzman C, Benet M, Pisonero-Vaquero S, et al. The human liver fatty acid binding protein (FABP1) gene is activated by FOXA1 and PPARalpha; and repressed by C/EBPalpha: implications in FABP1 down-regulation in nonalcoholic fatty liver disease. Biochim Biophys Acta. 2013;1831(4):803-818.

Wolfrum C, Borrmann CM, Borchers T, Spener F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha- and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci USA. 2001;98(5):2323-2328.

Peng XE, Wu YL, Lu QQ, Hu ZJ, Lin X. Two genetic variants in FABP1 and susceptibility to non-alcohol fatty liver disease in a Chinese population. Gene. 2012;500(1):54-58.

Mansego ML, Martinez F, Martinez-Larrad MT, et al. Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population. PLoS One. 2012;7(3):e31853.

Inoue M, Takahashi Y, Fujii T, Kitagawa M, Fukusato T. Significance of downregulation of liver fatty acid-binding protein in hepatocellular carcinoma. World J Gastroenterol. 2014;20(46):17541-17551.

Meixiong J, Dong X. Mas-related G protein-coupled receptors and the biology of itch sensation. Annu Rev Genet. 2017;51:103-121.

Meixiong J, Vasavda C, Green D, et al. Identification of a bilirubin receptor that may mediate a component of cholestatic itch. eLife. 2019;8:44116.

Yu H, Zhao T, Liu S, et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. eLife. 2019;8:48431.

Meixiong J, Vasavda C, Snyder SH, Dong X. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus. Proc Natl Acad Sci USA. 2019;116(21):10525-10530.

Ali H. Emerging roles for MAS-related G protein-coupled receptor-X2 in host defense peptide, opioid, and neuropeptide-mediated inflammatory reactions. Adv Immunol. 2017;136:123-162.

Bader M, Alenina N, Andrade-Navarro MA, Santos RA. MAS and its related G protein-coupled receptors, Mrgprs. Pharmacol Rev. 2014;66(4):1080-1105.

Solinski HJ, Gudermann T, Breit A. Pharmacology and signaling of MAS-related G protein-coupled receptors. Pharmacol Rev. 2014;66(3):570-597.

Gembardt F, Grajewski S, Vahl M, Schultheiss HP, Walther T. Angiotensin metabolites can stimulate receptors of the Mas-related genes family. Mol Cell Biochem. 2008;319(1-2):115-123.

Mortada I. Hyperbilirubinemia, hypertension, and CKD: the links. Curr Hypertens Rep. 2017;19(7):58.

Wang L, Bautista LE. Serum bilirubin and the risk of hypertension. Int J Epidemiol. 2015;44(1):142-152.

Goessling W, Zucker SD. Role of apolipoprotein D in the transport of bilirubin in plasma. Am J Physiol Gastrointest Liver Physiol. 2000;279(2):G356-G365.

Ganfornina MD, Do Carmo S, Lora JM, et al. Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging Cell. 2008;7(4):506-515.

Peitsch MC, Boguski MS. Is apolipoprotein D a mammalian bilin-binding protein? New Biol. 1990;2(2):197-206.

Beuckmann CT, Aoyagi M, Okazaki I, et al. Binding of biliverdin, bilirubin, and thyroid hormones to lipocalin-type prostaglandin D synthase. Biochemistry. 1999;38(25):8006-8013.

Soiland H, Soreide K, Janssen EA, Korner H, Baak JP, Soreide JA. Emerging concepts of apolipoprotein D with possible implications for breast cancer. Cell Oncol. 2007;29(3):195-209.

Weech PK, Provost P, Tremblay NM, et al. Apolipoprotein D-an atypical apolipoprotein. Prog Lipid Res. 1991;30(2-3):259-266.

Rassart E, Bedirian A, Do Carmo S, et al. Apolipoprotein D. Biochim Biophys Acta. 2000;1482(1-2):185-198.

Zelenka J, Muchova L, Zelenkova M, et al. Intracellular accumulation of bilirubin as a defense mechanism against increased oxidative stress. Biochimie. 2012;94(8):1821-1827.

Nofer JR. Signal transduction by HDL: agonists, receptors, and signaling cascades. Handb Exp Pharmacol. 2015;224:229-256.

Stoeckius M, Erat A, Fujikawa T, et al. Essential roles of Raf/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, YY1, and Ca2+ influx in growth arrest of human vascular smooth muscle cells by bilirubin. J Biol Chem. 2012;287(19):15418-15426.

Ollinger R, Bilban M, Erat A, et al. Bilirubin-a natural inhibitor of vascular smooth muscle cell proliferation. Circulation. 2005;112(7):1030-1038.

Jin D, El Tanani M, Campbell FC. Identification of apolipoprotein D as a novel inhibitor of osteopontin-induced neoplastic transformation. Int J Oncol. 2006;29(6):1591-1599.

Zucker SD, Qin XF, Yu F, Goessling W. Inhibition of breast cancer cell proliferation by unconjugated bilirubin is associated with enhanced expression of apolipoprotein D and increased nuclear translocation of transcription factor NF-kappa B. Hepatology. 1999;30(4):498A.

Perdomo G, Henry Dong H. Apolipoprotein D in lipid metabolism and its functional implication in atherosclerosis and aging. Aging. 2009;1(1):17-27.

Zelenka J, Dvorak A, Alan L, Zadinova M, Haluzik M, Vítek L. Hyperbilirubinemia protects against aging-associated inflammation and metabolic deterioration. Oxid Med Cell Long. 2016;2016:6190609-6190610.

Thomas EA, Dean B, Pavey G, Sutcliffe JG. Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: implications for the pathophysiology of psychiatric disorders. Proc Natl Acad Sci USA. 2001;98(7):4066-4071.

Bajo-Graneras R, Sanchez D, Gutierrez G, et al. Apolipoprotein D alters the early transcriptional response to oxidative stress in the adult cerebellum. J Neurochem. 2011;117(6):949-960.

Lai CJ, Cheng HC, Lin CY, et al. Activation of liver X receptor suppresses angiogenesis via induction of ApoD. FASEB J. 2017;31(12):5568-5576.

Mooberry LK, Sabnis NA, Panchoo M, Nagarajan B, Lacko AG. Targeting the SR-B1 receptor as a gateway for cancer therapy and imaging. Front Pharmacol. 2016;7:466.

Fujii M, Inoguchi T, Sasaki S, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int. 2010;78(9):905-919.

Lanone S, Bloc S, Foresti R, et al. Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J. 2005;19(13):1890-1892.

Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82(1):47-95.

Stec DE, Storm MV, Pruett BE, Gousset MU. Antihypertensive actions of moderate hyperbilirubinemia: role of superoxide inhibition. Am J Hypertens. 2013;26(7):918-923.

Kaasik K, Lee CC. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature. 2004;430(6998):467-471.

Oren DA. Humoral phototransduction: blood is a messenger. Neuroscientist. 1996;2(4):207-210.

Quail PH, Boylan MT, Parks BM, Short TW, Xu Y, Wagner D. Phytochromes: photosensory perception and signal transduction. Science. 1995;268(5211):675-680.

Wang S, Lin Y, Zhou Z, et al. Circadian clock gene Bmal1 regulates bilirubin detoxification: a potential mechanism of feedback control of hyperbilirubinemia. Theranostics. 2019;9(18):5122-5133.

Larsson A, Hassan M, Ridefelt P, Axelsson J. Circadian variability of bilirubin in healthy men during normal sleep and after an acute shift of sleep. Chronobiol Int. 2009;26(8):1613-1621.

Sennels HP, Jorgensen HL, Goetze JP, Fahrenkrug J. Rhythmic 24-hour variations of frequently used clinical biochemical parameters in healthy young males-the Bispebjerg study of diurnal variations. Scand J Clin Lab Invest. 2012;72(4):287-295.

Pocock SJ, Ashby D, Shaper AG, Walker M, Broughton PM. Diurnal variations in serum biochemical and haematological measurements. J Clin Pathol. 1989;42(2):172-179.

Kanabrocki EL, Sothern RB, Scheving LE, et al. Ten-year-replicated circadian profiles for 36 physiological, serological and urinary variables in healthy men. Chronobiol Int. 1988;5(3):237-284.

Claustrat B, Leston J. Melatonin: physiological effects in humans. Neurochirurgie. 2015;61(2-3):77-84.

Campbell SS, Murphy PJ. Extraocular circadian phototransduction in humans. Science. 1998;279(5349):396-399.

Oren DA, Terman M. Tweaking the human circadian clock with light. Science. 1998;279(5349):333-334.

Oren DA. Bilirubin, REM sleep, and phototransduction of environmental time cues. A hypothesis. Chronobiol Int. 1997;14:319-329.

Mirmiran M. The function of fetal/neonatal rapid eye movement sleep. Behav Brain Res. 1995;69(1-2):13-22.

Montorzi M, Dziedzic TS, Falchuk KH. Biliverdin during Xenopus laevis oogenesis and early embryogenesis. Biochemistry. 2002;41(31):10115-10122.

Makos BK, Youson JH. Serum levels of bilirubin and biliverdin in the sea lamprey, Petromyzon marinus L., before and after their biliary atresia. Comp Biochem Physiol A. 1987;87:761-764.

Wardle EN, Williams R. Depressed uptake of serotonin by platelets in hepatic encephalopathy. Biochem Med. 1980;24(2):223-227.

Menculini G, Verdolini N, Murru A, et al. Depressive mood and circadian rhythms disturbances as outcomes of seasonal affective disorder treatment: a systematic review. J Affect Disord. 2018;241:608-626.

Shimba S, Watabe Y. Crosstalk between the AHR signaling pathway and circadian rhythm. Biochem Pharmacol. 2009;77(4):560-565.

Friedlander AH, Bostrom KI, Tran HA, Chang TI, Polanco JC, Lee UK. Severe sleep apnea associated with increased systemic inflammation and decreased serum bilirubin. J Oral Maxillofac Surg. 2019;77(11):2318-2323.

Oren DA, Desan PH, Boutros N, Anand A, Charney DS. Effects of light on low nocturnal bilirubin in winter depression: a preliminary report. Biol Psychiatry. 2002;51(5):422-425.

Peng YF, Xiang Y, Wei YS. The significance of routine biochemical markers in patients with major depressive disorder. Sci Rep. 2016;6:34402.

Vítek L, Bellarosa C, Tiribelli C. Induction of mild hyperbilirubinemia: hype or real therapeutic opportunity? Clin Pharmacol Ther. 2019;106(3):568-575.

Lee Y, Lee S, Lee DY, Yu B, Miao W, Jon S. Multistimuli-responsive bilirubin nanoparticles for anticancer therapy. Angew Chem Int Ed Engl. 2016;55(36):10676-10680.

Lee Y, Lee S, Jon S. Biotinylated bilirubin nanoparticles as a tumor microenvironment-responsive drug delivery system for targeted cancer therapy. Adv Sci. 2018;1800017:1-8.

Lee DY, Kim JY, Lee Y, et al. Black pigment gallstone-inspired platinum-chelated bilirubin nanoparticles for combined photoacoustic imaging and photothermal therapy of cancers. Angew Chem Int Ed Engl. 2017;56:13684-13688.

Lee Y, Kim H, Kang S, Lee J, Park J, Jon S. Bilirubin nanoparticles as a nanomedicine for anti-inflammation therapy. Angew Chem Int Ed Engl. 2016;55(26):7460-7463.

Bae IH, Park DS, Lee SY, et al. Bilirubin coating attenuates the inflammatory response to everolimus-coated stents. J Biomed Mater Res B Appl Biomater. 2018;106(4):1486-1495.

Photooxidation of Dipyrrinones: Reaction with Singlet Oxygen and Characterization of Reaction Intermediates

Risk of childhood cancer in infants treated with phototherapy for neonatal jaundice

A Platform for the Synthesis of Oxidation Products of Bilirubin

Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases

Association of Low Serum Bilirubin Concentrations and Promoter Variations in the UGT1A1 and HMOX1 Genes with Type 2 Diabetes Mellitus in the Czech Population

The physiology of bilirubin: health and disease equilibrium

Serum Bilirubin and Markers of Oxidative Stress and Inflammation in a Healthy Population and in Patients with Various Forms of Atherosclerosis

Serum Bilirubin Concentrations and the Prevalence of Gilbert Syndrome in Elite Athletes

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

Cutting edge concepts: Does bilirubin enhance exercise performance?

Association of Serum Bilirubin and Functional Variants of Heme Oxygenase 1 and Bilirubin UDP-Glucuronosyl Transferase Genes in Czech Adult Patients with Non-Alcoholic Fatty Liver Disease

Diagnostic methods for neonatal hyperbilirubinemia: benefits, limitations, requirements, and novel developments

The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers

The Role of Bilirubin and the Other "Yellow Players" in Neurodegenerative Diseases