The role of bilirubin in diabetes, metabolic syndrome and cardiovascular diseases
Authors:
Libor Vítek
Authors‘ workplace:
IV. interní klinika a Ústav lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFN v Praze
Published in:
AtheroRev 2019; 4(2): 82-85
Category:
Reviews
Overview
For long time bilirubin was considered only an ominous sign of liver diseases. However, based on recent research, bilirubin is nowadays known as a potent antioxidant molecule, possessing additional biological activities. Bilirubin is a powerful anti-inflammatory compound, modulates number of intracelullar signaling pathways, affects protein phosphorylation. All these mechanisms may account for the protective effects of bilirubin against development of many civilization diseases. Its salutary effects on atherogenesis are generally accepted, but its serum concentrations have negative relationship also to risk of diabetes, obesity, arterial hypertension, metabolic syndrome or non-alcoholic steatohepatitis. Based on clinical studies, it is clear now that each micromolar increase of serum bilirubin concentrations is associated with significant health benefits. Subjects with mildly elevated serum bilirubin concentrations, such in Gilbert syndrome (benign hyperbilirubinemia), have much lower risk of these diseases, whereas those with low serum bilirubin levels are at much higher risk.
Keywords:
diabetes – antioxidant – bilirubin – Gilbert syndrome – cardiovascular diseases – risk factor
Sources
- Stocker R, Yamamoto Y, McDonagh AF et al. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235(4792): 1043–1046.
- Gazzin S, Vitek L, Watchko J et al. A novel perspective on the biology of bilirubin in health and disease. Trends Mol Med 2016; 22(9): 758–768. Dostupné z DOI: <http://dx.doi.org/10.1016/j.molmed.2016.07.004>.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1042/CS20140566>.
- Gazzin S, Masutti F, Vitek L et al. The molecular basis of jaundice: An old symptom revisited. Liver Int 2017; 37(8): 1094–1102. Dostupné z DOI: <http://dx.doi.org/10.1111/liv.13351>.
- Hansen TW, Mathiesen SB, Walaas SI. Bilirubin has widespread inhibitory effects on protein phosphorylation. Pediatr Res 1996; 39(6): 1072–1077. Dostupné z DOI: <http://dx.doi.org/10.1203/00006450–199606000–00023>.
- Vianello E, Zampieri S, Marcuzzo T et al. Histone acetylation as a new mechanism for bilirubin-induced encephalopathy in the Gunn rat. Sci Rep 2018; 8(1): 13690. Dostupné z DOI: <http://dx.doi.org/10.1038/s41598–018–32106-w>.
- Bulmer AC, Verkade HJ, Wagner KH. Bilirubin and beyond: a review of lipid status in Gilbert‘s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 2013; 52(2): 193–205. Dostupné z DOI: <http://dx.doi.org/10.1016/j.plipres.2012.11.001>.
- Schwertner HA, Fischer JR Jr. Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease. Atherosclerosis 2000; 150(2): 381–387.
- Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert‘s syndrome? Atherosclerosis 2015; 239(1): 73–84. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.042>.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1016/j.biocel.2013.09.014>
- Vitek L. Bilirubin and atherosclerotic diseases. Physiol Res 2017; 66(Suppl 1): S11-S20.
- Vitek L, Jirsa M, Brodanova M et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 2002; 160(2): 449–456.
- Novotny L, Vitek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med 2003; 228(5): 568–571.
- Shepherd RE, Moreno FJ, Cashore WJ et al. Effects of bilirubin on fat cell metabolism and lipolysis. Am J Physiol 1979; 237(6): E504-E508. Dostupné z DOI: <http://dx.doi.org/10.1152/ajpendo.1979.237.6.E504>.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1210/en.2013–1667>.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1038/srep09886>. Erratum in Corrigendum: Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels. [Sci Rep. 2016]
- Stec DE, John K, Trabbic CJ et al. Bilirubin binding to PPARalpha inhibits lipid accumulation. PLoS One 2016; 11(4): e0153427. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pone.0153427>.
- 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.
- Lu P, Yan J, Liu K et al. Activation of aryl hydrocarbon receptor dissociates fatty liver from insulin resistance by inducing fibroblast growth factor 21. Hepatology 2015; 61(6): 1908–1919. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.27719>.
- Vitek L, Haluzik M. The role of bile acids in metabolic regulation. J Endocrinol 2016; 228(3): R85-R96. Dostupné z DOI: <http://dx.doi.org/10.1530/JOE-15–0469>.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1038/ncomms5573>.
- Fu YY, Kang KJ, Ahn JM, et al. Hyperbilirubinemia reduces the streptozotocin-induced pancreatic damage through attenuating the oxidative stress in the Gunn rat. Tohoku J Exp Med 2010; 222(4): 265–273.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1038/ki.2010.265>.
- Vitek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol 2012; 3: 55. Dostupné z DOI: <http://dx.doi.org/10.3389/fphar.2012.00055>.
- Ko GT, Chan JC, Woo J et al. Serum bilirubin and cardiovascular risk factors in a Chinese population. J Cardiovasc Risk 1996; 3(5): 459–463.
- Fukui M, Tanaka M, Yamazaki M, et al. Low serum bilirubin concentration in haemodialysis patients with Type 2 diabetes. Diabet Med 2011; 28(1): 96–99.
- Inoguchi T, Sasaki S, Kobayashi K, et al. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA 2007; 298(12): 1398–1400. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.298.12.1398-b>.
- Kalousova M, Novotny L, Zima T et al. Decreased levels of advanced glycation end-products in patients with Gilbert syndrome. Cell Mol Biol 2005; 51(4): 387–392.
- Cheriyath P, Gorrepati VS, Peters I et al. High total bilirubin as a protective factor for diabetes mellitus: An analysis of NHANES data from 1999 – 2006. J Clin Med Res 2010; 2(5): 201–206. Dostupné z DOI: <http://dx.doi.org/10.4021/jocmr425w>.
- Yasuda M, Kiyohara Y, Wang JJ et al. High serum bilirubin levels and diabetic retinopathy. The Hisayama Study. Ophthalmology 2011; 118(7): 1423–1428. Dostupné z DOI: <http://dx.doi.org/10.1016/j.ophtha.2010.12.009>.
- Han SS, Na KY, Chae DW et al. High serum bilirubin is associated with the reduced risk of diabetes mellitus and diabetic nephropathy. Tohoku J Exp Med 2010; 221(2): 133–140.
- Riphagen IJ, Deetman PE, Bakker SJ et al. Bilirubin and progression of nephropathy in type 2 diabetes: A post hoc analysis of RENAAL with independent replication in IDNT. Diabetes 2014; 63(8): 2845–2853. Dostupné z DOI: <http://dx.doi.org/10.2337/db13–1652>.
- Wu Y, Zhang J, Wang J et al. The association of serum bilirubin on kidney clinicopathologic features and renal outcome in patients with diabetic nephropathy: A biopsy-based study. Endocr Pract 2019. Dostupné z DOI: <http://dx.doi.org/10.4158/EP-2018–0560>.
- Chan KH, O‘Connell RL, Sullivan DR et al. Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 2013; 56(4): 724–736. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–012–2818–4>.
- Bossard M, Aeschbacher S, Schoen T et al. Serum bilirubin levels and risk of prediabetes in young and healthy adults. Int J Cardiol 2014; 171(2): e24–25. Dostupné z DOI: <http://dx.doi.org/10.1016/j.ijcard.2013.11.125>.
- Fukui M, Tanaka M, Shiraishi E et al. Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int 2008; 74(9): 1197–1201. Dostupné z DOI: <http://dx.doi.org/10.1038/ki.2008.398>.
- Oda E. Bilirubin is negatively associated with A1C independently of fasting plasma glucose, age, obesity, inflammation, hemoglobin, and iron in apparently healthy Japanese men and women. Diabetes Care 2010; 33(10): e131. Dostupné z DOI: <http://dx.doi.org/10.2337/dc10–1246>.
- Ohnaka K, Kono S, Inoguchi T et al. Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res Clin Pract 2010; 88(1): 103–110. Dostupné z DOI: <http://dx.doi.org/10.1016/j.diabres.2009.12.022>.
- Oda E, Kawai R. Bilirubin is negatively associated with hemoglobin a(1c) independently of other cardiovascular risk factors in apparently healthy Japanese men and women. Circ J 2011; 75(1): 190–195.
- Lin LY, Kuo HK, Hwang JJ et al. Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents. Atherosclerosis 2009; 203(2): 563–568. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2008.07.021>.
- Kwon K-M, Kam J-H, Kim M-Y et al. Inverse association between total bilirubin and metabolic syndrome in rural Korean women. J Womens Health 2011; 20(6): 963–969. Dostupné z DOI: <http://dx.doi.org/10.1089/jwh.2010.2453>.
- Wu Y, Li M, Xu M et al. Low serum total bilirubin concentrations are associated with increased prevalence of metabolic syndrome in Chinese. J Diabetes 2011; 3(3): 217–224. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1753–0407.2011.00138.x>.
- Deetman PE, Bakker SJ, Kwakernaak AJ et al. The relationship of the anti-oxidant bilirubin with free thyroxine is modified by insulin resistance in euthyroid subjects. PLoS One 2014; 9(3): e90886. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pone.0090886>.
- Choi SH, Yun KE, Choi HJ. Relationships between serum total bilirubin levels and metabolic syndrome in Korean adults. Nutr Metab Cardiovasc Dis 2013; 23(1): 31–37. Dostupné z DOI: <http://dx.doi.org/10.1016/j.numecd.2011.03.001>.
- Bhuiyan AR, Srinivasan SR, Chen W et al. Association of serum bilirubin with pulsatile arterial function in asymptomatic young adults: the Bogalusa Heart Study. Metabolism 2008; 57(5): 612–616. Dostupné z DOI: <http://dx.doi.org/10.1016/j.metabol.2007.12.003>.
- 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. Dostupné z DOI: <http://dx.doi.org/10.1016/j.metabol.2009.04.003>.
- Jenko-Praznikar Z, Petelin A, Jurdana M et al. Serum bilirubin levels are lower in overweight asymptomatic middle-aged adults: An early indicator of metabolic syndrome? Metabolism 2013; 62(7): 976–985. Dostupné z DOI: <http://dx.doi.org/10.1016/j.metabol.2013.01.011>.
- Guzek M, Jakubowski Z, Bandosz P et al. Inverse association of serum bilirubin with metabolic syndrome and insulin resistance in Polish population. Przegl Epidemiol 2012; 66(3): 495–501.
- Lin Y-C, Chang P-F, Hu F-C et al. Variants in the UGT1A1 gene and the risk of pediatric nonalcoholic fatty liver disease. Pediatrics 2009; 124(6): E1221-E1227. Dostupné z DOI: <http://dx.doi.org/10.1542/peds.2008–3087>.
- Puri K, Nobili V, Melville K et al. Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2013; 57(1): 114–118. Dostupné z DOI: <http://dx.doi.org/10.1097/MPG.0b013e318291fefe>.
- O‘Neill S, O‘Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 2015; 16(1): 1–12. Dostupné z DOI: <http://dx.doi.org/10.1111/obr.12229>.
- Seyed Khoei N, Grindel A, Wallner M et al. Mild hyperbilirubinaemia as an endogenous mitigator of overweight and obesity: Implications for improved metabolic health. Atherosclerosis 2018; 269: 306–311. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2017.12.021>.
- Bulmer AC, Bakrania B, Boon AC et al. Bilirubin: A Novel Endogenous Hypolipidemic and Hypotensive Agent Preventing Cardiovascular Disease. Hypertension 2014; 63(6): E157-E157.
- Boon AC, Bulmer AC, Coombes JS et al. Circulating bilirubin and defense against kidney disease and cardiovascular mortality:mechanisms contributing to protection in clinical investigations. Am J Physiol Renal Physiol 2014; 307(2): F123–36. Dostupné z DOI: <http://dx.doi.org/10.1152/ajprenal.00039.2014>.
- Dullaart RP, Boersema J, Lefrandt JD et al. The inverse association of incident cardiovascular disease with plasma bilirubin is unaffected by adiponectin. Atherosclerosis 2014; 235(2): 380–383. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2014.05.938>.
- Kubota N, Terauchi Y, Yamauchi T et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002; 277(29): 25863–25866. Dostupné z DOI: <http://dx.doi.org/10.1074/jbc.C200251200>.
- Cure E, Cicek Y, Cumhur Cure M et al. The evaluation of relationship between adiponectin levels and epicardial adipose tissue thickness with low cardiac risk in Gilbert`s syndrome: an observational study. Anadolu Kardiyol Derg 2013; 13(8): 791–796. Dostupné z DOI: <http://dx.doi.org/10.5152/akd.2013.266>.
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