Bilirubin and beyond: A review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection

Progress in Lipid Research

Volumn 52, Issue 2, 2013, Pages 193-205

  Bulmer, A C ^a   Verkade, H J ^b   Wagner, K H ^a,c  

^a GRIFFITH UNIVERSITY   (Australia)

^b UNIVERSITY OF GRONINGEN   (Netherlands)

^c UNIVERSITY OF VIENNA   (Austria)

Author keywords

Aryl hydrocarbon receptor; Bile pigment; Cholesterol; Crigler Najjar syndrome; Gunn rat; Heme oxygenase; Obesity; Phosopholipid; Triacylglycerol

Indexed keywords

AROMATIC HYDROCARBON RECEPTOR; BILIRUBIN; CHOLESTEROL; HEME OXYGENASE 1; HEME OXYGENASE 2; LIPID; MACROGOL; MULTIDRUG RESISTANCE PROTEIN 2; ORGANIC ANION TRANSPORTER; PHENOBARBITAL; SIBUTRAMINE; TAUROCHOLIC ACID; TETRAHYDROLIPSTATIN; TRIACYLGLYCEROL;

BILIARY EXCRETION; BILIRUBIN BLOOD LEVEL; BILIRUBIN METABOLISM; BODY MASS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CRIGLER NAJJAR SYNDROME; DUBIN JOHNSON SYNDROME; ENZYME ACTIVITY; GILBERT DISEASE; HEART PROTECTION; HEMODIALYSIS PATIENT; HOMEOSTASIS; HUMAN; HYPERBILIRUBINEMIA; INTESTINE; KIDNEY; LIPID ANALYSIS; LIPID METABOLISM; LIPOPROTEIN SYNTHESIS; LIVER; METABOLIC REGULATION; NONHUMAN; PATHOPHYSIOLOGY; PHOTOTHERAPY; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN SECRETION; REVIEW; SEX DIFFERENCE; TRIACYLGLYCEROL BLOOD LEVEL;

ANIMALS; BILIRUBIN; CARDIOVASCULAR DISEASES; GILBERT DISEASE; HUMANS; LIPID METABOLISM;

ANIMALIA; RATTUS NORVEGICUS;

EID: 84875750146     PISSN: 01637827     EISSN: 18732194     Source Type: Journal    
DOI: 10.1016/j.plipres.2012.11.001     Document Type: Review

References (131)

1. M. Kaplan, and C. Hammerman Neonatal screening for glucose-6-phosphate dehydrogenase deficiency: biochemical versus genetic technologies Semin Perinatol 35 2011 155 161
2. H. Ihara, N. Hashizume, N. Shimizu, and T. Aoki Threshold concentration of unbound bilirubin to induce neurological deficits in a patient with type I Crigler-Najjar syndrome Ann Clin Biochem 36 Pt. 3 1999 347 352 (Pubitemid 29248528)
3. A.C. Bulmer, J.T. Blanchfield, I. Toth, R.G. Fassett, and J.S. Coombes Improved resistance to serum oxidation in Gilbert's syndrome: a mechanism for cardiovascular protection Atherosclerosis 199 2008 390 396
4. R. Stocker, Y. Yamamoto, A.F. McDonagh, A.N. Glazer, and B.N. Ames Bilirubin is an antioxidant of possible physiological importance Science 235 1987 1043 1046 (Pubitemid 17049750)
5. R. Stocker Antioxidant activities of bile pigments Antioxid Redox Signal 6 2004 841 849 (Pubitemid 39237937)
6. H.A. Schwertner, W.G. Jackson, and G. Tolan Association of low serum concentration of bilirubin with increased risk of coronary artery disease Clin Chem 40 1994 18 23 (Pubitemid 24050206)
7. L. Vitek, M. Jirsa, M. Brodanova, M. Kalab, Z. Marecek, and V. Danzig Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels Atherosclerosis 160 2002 449 456 (Pubitemid 34159340)
8. K.Y. Fertrin, M.S. Goncalves, S.T. Saad, and F.F. Costa Frequencies of UDP-glucuronosyltransferase 1 (UGT1A1) gene promoter polymorphisms among distinct ethnic groups from Brazil Am J Med Genet 108 2002 117 119
9. L. Muchova, K. Vanova, J. Zelenka, M. Lenicek, T. Petr, and M. Vejrazka Bile acids decrease intracellular bilirubin levels in the cholestatic liver: implications for bile acid-mediated oxidative stress J Cell Mol Med 15 2011 1156 1165
10. P.A. Dennery, A.F. McDonagh, D.R. Spitz, P.A. Rodgers, and D.K. Stevenson Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia Free Radic Biol Med 19 1995 395 404
11. Z. Yesilova, M. Serdar, C.N. Ercin, A. Gunay, G. Kilciler, and A. Hasimi Decreased oxidation susceptibility of plasma low density lipoproteins in patients with Gilbert's syndrome J Gastroenterol Hepatol 23 2008 1556 1560
12. P.R. Nolting, D.M. Kusters, B.A. Hutten, and J.J. Kastelein Serum bilirubin levels in familial hypercholesterolemia: a new risk marker for cardiovascular disease? J Lipid Res 52 2011 1755 1759
13. A.-C. Boon, C.L. Hawkins, K. Bisht, B. Bakrania, J.S. Coombes, and K.-H. Wagner Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert's syndrome Free Radic Biol Med 52 2012 2120 2127
14. I. Ocadlik, S. Hlinstakova, and S. Oravec Relationship between unconjugated hyperbilirubinemia and lipoprotein spectrum Neuro Endocrinol Lett 32 2011 360 364
15. Wallner M, Marculescu R, Doberer D, Vitek L, Bulmer AC, Wagner KH. Cardiovascular protection in subjects with Gilbert syndrome: a significant effect of bilirubin on lipid metabolism unpublished results.
16. J. Fevery Bilirubin in clinical practice: a review Liver Int 28 2008 592 605 (Pubitemid 351541090)
17. M.D. Maines, and N. Panahian The heme oxygenase system and cellular defense mechanisms. Do HO-1 and HO-2 have different functions? Adv Exp Med Biol 502 2001 249 272 (Pubitemid 34234060)
18. H.P. Kim, H.O. Pae, S.H. Back, S.W. Chung, J.M. Woo, and Y. Son Heme oxygenase-1 comes back to endoplasmic reticulum Biochem Biophys Res Commun 404 2011 1 5
19. L. Vitek, and H.A. Schwertner The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases Adv Clin Chem 43 2007 1 57 (Pubitemid 44960959)
20. L. Minchiotti, M. Galliano, M.C. Zapponi, and R. Tenni The structural characterization and bilirubin-binding properties of albumin herborn, a [Lys240→Glu] albumin mutant Eur J Biochem 214 1993 437 444 (Pubitemid 23173793)
21. T. Kamisako, Y. Kobayashi, K. Takeuchi, T. Ishihara, K. Higuchi, and Y. Tanaka Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance J Gastroenterol 35 2000 659 664
22. S.D. Zucker, W. Goessling, and A.G. Hoppin Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers and native hepatocyte membranes J Biol Chem 274 1999 10852 10862 (Pubitemid 29191067)
23. A.D. Mottino, J.M. Pellegrino, E.E. Guibert, M.G. Roma, and E.A. Rodriguez Garay Comparison of hepatic, renal and intestinal bilirubin UDP-glucuronyl transferase activities in rat microsomes Int J Biochem 20 1988 1113 1116
24. J. Rothuizen Important clinical syndromes associated with liver disease Vet Clin North Am Small Anim Pract 39 2009 419 437
25. M.M. Elias, E.J. Comin, E.J. Ochoa, and E.A. Rodriguez Garay Evidence for a secretory component in the handling of unconjugated bilirubin by the isolated perfused rat kidney Can J Physiol Pharmacol 63 1985 1581 1585 (Pubitemid 16164361)
26. M.M. Elias, A.D. Mottino, and E.J. Ochoa Transepithelial fate of bilirubin in the isolated rat kidney Biochim Biophys Acta 1336 1997 7 14 (Pubitemid 27300156)
27. L. Vitek, I. Kraslova, L. Muchova, L. Novotny, and T. Yamaguchi Urinary excretion of oxidative metabolites of bilirubin in subjects with Gilbert syndrome J Gastroenterol Hepatol 22 2007 841 845 (Pubitemid 46911019)
28. M.M. Elias, E.J. Comin, J.E. Ochoa, and G.A. Rodriguez Garay Renal handling of bilirubin photoderivatives Experientia 43 1987 875 878
29. Y. Tanaka, Y. Kobayashi, E.C. Gabazza, K. Higuchi, T. Kamisako, and M. Kuroda Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice Am J Physiol Gastrointest Liver Physiol 282 2002 G656 G662
30. F.J. Cuperus, A.A. Iemhoff, M. van der Wulp, R. Havinga, and H.J. Verkade Acceleration of the gastrointestinal transit by polyethylene glycol effectively treats unconjugated hyperbilirubinaemia in gunn rats Gut 59 2010 373 380
31. S. Caglayan, H. Candemir, S. Aksit, S. Kansoy, S. Asik, and I. Yaprak Superiority of oral agar and phototherapy combination in the treatment of neonatal hyperbilirubinemia Pediatrics 92 1993 86 89 (Pubitemid 23188873)
32. A.M. Hafkamp, R. Nelisse-Haak, M. Sinaasappel, R.P. Oude Elferink, and H.J. Verkade Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial Pediatr Res 62 2007 725 730 (Pubitemid 350158814)
33. A.M. Hafkamp, R. Havinga, J.D. Ostrow, C. Tiribelli, L. Pascolo, and M. Sinaasappel Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: phototherapy and orlistat treatment in Gunn rats Pediatr Res 59 2006 506 512 (Pubitemid 43740047)
34. T. Nishioka, A.M. Hafkamp, R. Havinga, P.P. Vn Lierop, H. Velvis, and H.J. Verkade Orlistat treatment increases fecal bilirubin excretion and decreases plasma bilirubin concentrations in hyperbilirubinemic Gunn rats J Pediatr 143 2003 327 334 (Pubitemid 37188317)
35. A.C. Bulmer, J.T. Blanchfield, J.S. Coombes, and I. Toth In vitro permeability and stability of bile pigments and the effects of hydrophilic and lipophilic modification of biliverdin Bioorg Med Chem 16 2008 3616 3625 (Pubitemid 351484046)
36. A.C. Bulmer, J.S. Coombes, J.T. Blanchfield, I. Toth, R.G. Fasset, and S.M. Taylor Bile pigment phamacokinetics and absorption in the rat: therapeutic potential for enteral administration Br J Pharmacol 164 2011 1857 1870
37. T. Ishihara, M. Kaito, K. Takeuchi, E.C. Gabazza, Y. Tanaka, and K. Higuchi Role of UGT1A1 mutation in fasting hyperbilirubinemia J Gastroenterol Hepatol 16 2001 678 682 (Pubitemid 34188844)
38. C.P. Strassburg Pharmacogenetics of Gilbert's syndrome Pharmacogenomics 9 2008 703 715
39. P.J. Bosma, J.R. Chowdhury, C. Bakker, S. Gantla, A. de Boer, and B.A. Oostra The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome N Engl J Med 333 1995 1171 1175
40. C.P. Strassburg Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome) Best Pract Res Clin Gastroenterol 24 2010 555 571
41. M. Persico, E. Persico, C.T. Bakker, I. Rigato, A. Amoroso, and R. Torella Hepatic uptake of organic anions affects the plasma bilirubin level in subjects with Gilbert's syndrome mutations in UGT1A1 Hepatology 33 2001 627 632 (Pubitemid 32185225)
42. E. van de Steeg, V. Stranecky, H. Hartmannova, L. Noskova, M. Hrebicek, and E. Wagenaar Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver J Clin Invest 122 2012 519 528
43. S. D'Silva, V. Borse, R.B. Colah, K. Ghosh, and M.B. Mukherjee Association of (GT)n repeats promoter polymorphism of heme oxygenase-1 gene with serum bilirubin levels in healthy indian adults Genet Test Mol Biomarkers 15 2011 215 218
44. S. Immenschuh, Y. Shan, H. Kroll, S. Santoso, W. Wossmann, and G. Bein Marked hyperbilirubinemia associated with the heme oxygenase-1 gene promoter microsatellite polymorphism in a boy with autoimmune hemolytic anemia Pediatrics 119 2007 e764 e767
45. P.A. Dennery, D.S. Seidman, and D.K. Stevenson Neonatal hyperbilirubinemia N Engl J Med 344 2001 581 590
46. C.E. Ahlfors, R.P. Wennberg, J.D. Ostrow, and C. Tiribelli Unbound (free) bilirubin: improving the paradigm for evaluating neonatal jaundice Clin Chem 55 2009 1288 1299
47. J.F. Watchko Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns Neuromol Med 8 2006 513 529
48. R. Calligaris, C. Bellarosa, R. Foti, P. Roncaglia, P. Giraudi, and H. Krmac A transcriptome analysis identifies molecular effectors of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells BMC Genomics 10 2009 543
49. Z. Han, P. Hu, and D. Ni Bilirubin induced apoptosis of human neuroblastoma cell line SH-SY5Y and affected the mitochondrial membrane potential Zhonghua Er Bi Yan Hou Ke Za Zhi 37 2002 243 246
50. P. Ahmed, A. Pratt, V.J. Land, M.W. Flye, and H. Chaplin Multiple plasma exchanges successfully maintain a young adult patient with Crigler-Najjar syndrome type I J Clin Apher 5 1989 17 20 (Pubitemid 19208962)
51. J. Ramirez, B.J. Komoroski, S. Mirkov, A.Y. Graber, D.L. Fackenthal, and E.G. Schuetz Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes Pharmacogenet Genomics 16 2006 79 86 (Pubitemid 43145676)
52. P.L. Jansen Diagnosis and management of Crigler-Najjar syndrome Eur J Pediatr 158 Suppl 2 1999 S89 S94
53. D. Morioka, M. Kasahara, Y. Takada, J.P. Corrales, A. Yoshizawa, and S. Sakamoto Living donor liver transplantation for pediatric patients with inheritable metabolic disorders Am J Transplant 5 2005 2754 2763
54. C.C. Paulusma, P.J. Bosma, G.J. Zaman, C.T. Bakker, M. Otter, and G.L. Scheffer Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene Science 271 1996 1126 1128 (Pubitemid 26075228)
55. T. Maruhashi, J. Soga, N. Fujimura, N. Idei, S. Mikami, and Y. Iwamoto Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome Circulation 126 2012 598 603
56. S. Tapan, N. Karadurmus, T. Dogru, C.N. Ercin, I. Tasci, and C. Bilgi Decreased small dense LDL levels in Gilbert's syndrome Clin Biochem 44 2011 300 303
57. L. Smiderle, A.C. Galvao, C. Fontana, M.C. Wender, G. Agnes, and M. Giovenardi Evaluation of UGT1A1 and SULT1A1 polymorphisms with lipid levels in women with different hormonal status Gynecol Endocrinol 27 2011 20 26
58. J.P. Lin, C.J. O'Donnell, J.P. Schwaiger, L.A. Cupples, A. Lingenhel, and S.C. Hunt Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study Circulation 114 2006 1476 1481 (Pubitemid 44527002)
59. N. Sneitz, K. Krishnan, D.F. Covey, and M. Finel Glucuronidation of the steroid enantiomers ent-17beta-estradiol, ent-androsterone and ent-etiocholanolone by the human UDP-glucuronosyltransferases J Steroid Biochem Mol Biol 127 2011 282 288
60. J. Zhou, T.S. Tracy, and R.P. Remmel Correlation between bilirubin glucuronidation and estradiol-3-gluronidation in the presence of model UDP-glucuronosyltransferase 1A1 substrates/inhibitors Drug Metab Dispos 39 2011 322 329
61. L.H. Breimer, G. Wannamethee, S. Ebrahim, and A.G. Shaper Serum bilirubin and risk of ischemic heart disease in middle-aged British men Clin Chem 41 1995 1504 1508
62. S.H. Choi, K.E. Yun, and H.J. Choi Relationships between serum total bilirubin levels and metabolic syndrome in Korean adults Nutr Metab Cardiovasc Dis 2011 [Epub ahead of print]
63. E.H.M. Temme, J. Zhang, E.G. Schouten, and H. Kesteloot Serum bilirubin and 10-year mortality risk in a Belgian population Cancer Causes Control 12 2001 887 894 (Pubitemid 34048869)
64. P.F. McArdle, B.W. Whitcomb, K. Tanner, B.D. Mitchell, A.R. Shuldiner, and A. Parsa Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference BMC Cardiovasc Disord 12 2012 16
65. A.R. Bhuiyan, S.R. Srinivasan, W. Chen, A. Sultana, and G.S. Berenson Association of serum bilirubin with pulsatile arterial function in asymptomatic young adults: the Bogalusa Heart Study Metabolism 57 2008 612 616 (Pubitemid 351608221)
66. G.T. Ko, J.C. Chan, J. Woo, E. Lau, V.T. Yeung, and C.C. Chow Serum bilirubin and cardiovascular risk factors in a Chinese population J Cardiovasc Risk 3 1996 459 463 (Pubitemid 27051345)
67. K.M. Kwon, J.H. Kam, M.Y. Kim, C.H. Chung, J.K. Kim, and J.A. Linton Inverse association between total bilirubin and metabolic syndrome in rural Korean women J Womens Health (Larchmt) 20 2011 963 969
68. H.J. Hwang, S.W. Lee, and S.H. Kim Relationship between bilirubin and C-reactive protein Clin Chem Lab Med 49 2011 1823 1828
69. H.J. Hwang, and S.H. Kim Inverse relationship between fasting direct bilirubin and metabolic syndrome in Korean adults Clin Chim Acta 411 2010 1496 1501
70. L.J. Horsfall, G. Rait, K. Walters, D.M. Swallow, S.P. Pereira, and I. Nazareth Serum bilirubin and risk of respiratory disease and death JAMA 305 2011 691 697
71. H.J. Chin, H.J. Cho, T.W. Lee, K.Y. Na, K.H. Oh, and K.W. Joo The mildly elevated serum bilirubin level is negatively associated with the incidence of end stage renal disease in patients with iga nephropathy J Korean Med Sci 24 Suppl. 2009 S22 S29
72. Y.H. Chen, S.C. Hung, and D.C. Tarng Serum bilirubin links UGT1A1*28 polymorphism and predicts long-term cardiovascular events and mortality in chronic hemodialysis patients Clin J Am Soc Nephrol 6 2011 567 574
73. J.S. Coombes, and R.G. Fassett Antioxidant therapy in hemodialysis patients: a systematic review Kidney Int 81 2012 233 246
74. C. Andersson, P. Weeke, E.L. Fosbol, B. Brendorp, L. Kober, and W. Coutinho 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 58 2009 1109 1115
75. S. Stender, R. Frikke-Schmidt, B.G. Nordestgaard, P. Grande, and A. Tybjaerg-Hansen Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis J Intern Med 2012
76. Johansen CT, Hegele RA. Using Mendelian randomization to determine causative factors in cardiovascular disease. J Intern Med 2012 [Epub ahead of print].
77. T. Iyanagi, T. Watanabe, and Y. Uchiyama The 3-methylcholanthrene- inducible UDP-glucuronosyltransferase deficiency in the hyperbilirubinemic rat (Gunn rat) is caused by a -1 frameshift mutation J Biol Chem 264 1989 21302 21307 (Pubitemid 20017951)
78. A.F. McDonagh, and L.A. Palma Hepatic excretion of circulating bilirubin photoproducts in the Gunn rat J Clin Invest 66 1980 1182 1185 (Pubitemid 11233823)
79. Y.Y. Fu, K.J. Kang, J.M. Ahn, H.R. Kim, K.Y. Na, and D.W. Chae Hyperbilirubinemia reduces the streptozotocin-induced pancreatic damage through attenuating the oxidative stress in the Gunn rat Tohoku J Exp Med 222 2010 265 273
80. S. Sakamoto, H. Kusuhara, K. Miyata, H. Shimaoka, T. Kanazu, and Y. Matsuo Glucuronidation converting methyl 1-(3,4-dimethoxyphenyl)-3-(3- ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoat e (S-8921) to a potent apical sodium-dependent bile acid transporter inhibitor, resulting in a hypocholesterolemic action J Pharmacol Exp Ther 322 2007 610 618 (Pubitemid 47105791)
81. R.H. Astolfi, D.D. Bugano, A.A. Francisco, M.M. de Souza, S.K. Ono-Nita, and E.C. Baracat Is Gilbert syndrome a new risk factor for breast cancer? Med Hypotheses 77 2011 162 164
82. S.L. Mumford, S. Dasharathy, A.Z. Pollack, and E.F. Schisterman Variations in lipid levels according to menstrual cycle phase: clinical implications Clin Lipidol 6 2011 225 234
83. S.L. Mumford, E.F. Schisterman, A.M. Siega-Riz, R.W. Browne, A.J. Gaskins, and M. Trevisan A longitudinal study of serum lipoproteins in relation to endogenous reproductive hormones during the menstrual cycle: findings from the biocycle study J Clin Endocrinol Metab 95 2010 E80 E85
84. G. Brufau, A.K. Groen, and F. Kuipers Reverse cholesterol transport revisited: contribution of biliary versus intestinal cholesterol excretion Arterioscler Thromb Vasc Biol 31 2011 1726 1733
85. A.E. van der Velde, G. Brufau, and A.K. Groen Transintestinal cholesterol efflux Curr Opin Lipidol 21 2010 167 171
86. J.K. Kruit, T. Plosch, R. Havinga, R. Boverhof, P.H. Groot, and A.K. Groen Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice Gastroenterology 128 2005 147 156 (Pubitemid 40039966)
87. A.E. van der Velde, C.L. Vrins, K. van den Oever, C. Kunne, R.P. Oude Elferink, and F. Kuipers Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice Gastroenterology 133 2007 967 975 (Pubitemid 47374133)
88. R. Schmid, and L. Hammaker Metabolism and disposition of C14-bilirubin in congenital nonhemolytic jaundice J Clin Invest 42 1963 1720 1734
89. G. Bortolussi, L. Zentilin, G. Baj, P. Giraudi, C. Bellarosa, and M. Giacca Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer FASEB J 26 2012 1052 1063
90. J.N. van der Veen, T.H. van Dijk, C.L. Vrins, H. van Meer, R. Havinga, and K. Bijsterveld Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol J Biol Chem 284 2009 19211 19219
91. K.W. Bock, and C. Kohle Contributions of the Ah receptor to bilirubin homeostasis and its antioxidative and atheroprotective functions Biol Chem 391 2010 645 653
92. D. Phelan, G.M. Winter, W.J. Rogers, J.C. Lam, and M.S. Denison Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin Arch Biochem Biophys 357 1998 155 163 (Pubitemid 28402597)
93. J. Abel, and T. Haarmann-Stemmann An introduction to the molecular basics of aryl hydrocarbon receptor biology Biol Chem 391 2010 1235 1248
94. P. Fernandez-Salguero, T. Pineau, D.M. Hilbert, T. McPhail, S.S. Lee, and S. Kimura Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor Science 268 1995 722 726
95. G.P. Lahvis, and C.A. Bradfield Ahr null alleles: distinctive or different? Biochem Pharmacol 56 1998 781 787 (Pubitemid 28458971)
96. J.V. Schmidt, G.H. Su, J.K. Reddy, M.C. Simon, and C.A. Bradfield Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development Proc Natl Acad Sci USA 93 1996 6731 6736 (Pubitemid 26230378)
97. R. Tanos, R.D. Patel, I.A. Murray, P.B. Smith, A.D. Patterson, and G.H. Perdew Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner Hepatology 55 2012 1994 2004
98. B.C. DiNatale, I.A. Murray, J.C. Schroeder, C.A. Flaveny, T.S. Lahoti, and E.M. Laurenzana Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling Toxicol Sci 115 2010 89 97
99. J.C. Schroeder, B.C. Dinatale, I.A. Murray, C.A. Flaveny, Q. Liu, and E.M. Laurenzana The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor Biochemistry 49 2010 393 400
100. P. Dabir, T.E. Marinic, I. Krukovets, and O.I. Stenina Aryl hydrocarbon receptor is activated by glucose and regulates the thrombospondin-1 gene promoter in endothelial cells Circ Res 102 2008 1558 1565
101. D.R. Boverhof, L.D. Burgoon, C. Tashiro, B. Sharratt, B. Chittim, and J.R. Harkema Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice Toxicol Sci 94 2006 398 416 (Pubitemid 44817156)
102. N. Fletcher, D. Wahlstrom, R. Lundberg, C.B. Nilsson, K.C. Nilsson, and K. Stockling 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the mRNA expression of critical genes associated with cholesterol metabolism, bile acid biosynthesis, and bile transport in rat liver: a microarray study Toxicol Appl Pharmacol 207 2005 1 24 (Pubitemid 41073756)
103. A.L. Forgacs, M.N. Kent, M.K. Makley, B. Mets, N. DelRaso, and G.L. Jahns Comparative metabolomic and genomic analyses of TCDD-elicited metabolic disruption in mouse and rat liver Toxicol Sci 125 2012 41 55
104. J. Kapitulnik, and F.J. Gonzalez Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat Mol Pharmacol 43 1993 722 725 (Pubitemid 23146270)
105. L. Vitek, and M.C. Carey New pathophysiological concepts underlying pathogenesis of pigment gallstones Clin Res Hepatol Gastroenterol 36 2 2011 122 129
106. S. Buch, C. Schafmayer, H. Volzke, M. Seeger, J.F. Miquel, and S.C. Sookoian Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition Gastroenterology 139 2010 1942 1951 e2
107. H.J. Verkade Inhibition of biliary phospholipid and cholesterol secretion by organic anions affects bile canalicular membrane composition and fluidity J Gastroenterol 35 2000 481 485 (Pubitemid 30427128)
108. H.J. Verkade, M.J. Wolbers, R. Havinga, D.R. Uges, R.J. Vonk, and F. Kuipers The uncoupling of biliary lipid from bile acid secretion by organic anions in the rat Gastroenterology 99 1990 1485 1492 (Pubitemid 20381889)
109. M.D. Apstein Inhibition of biliary phospholipid and cholesterol secretion by bilirubin in the Sprague-Dawley and Gunn rat Gastroenterology 87 1984 634 638 (Pubitemid 14061418)
110. H.J. Verkade, R. Havinga, A. Gerding, R.J. Vonk, and F. Kuipers Mechanism of bile acid-induced biliary lipid secretion in the rat: effect of conjugated bilirubin Am J Physiol 264 1993 G462 G469
111. H.J. Verkade, H. Wolters, A. Gerding, R. Havinga, V. Fidler, and R.J. Vonk Mechanism of biliary lipid secretion in the rat: a role for bile acid-independent bile flow? Hepatology 17 1993 1074 1080 (Pubitemid 23187414)
112. H.J. Verkade, M.A. de Bruijn, M.A. Brink, H. Talsma, R.J. Vonk, and F. Kuipers Interactions between organic anions, micelles and vesicles in model bile systems Biochem J 320 Pt. 3 1996 917 923 (Pubitemid 27013810)
113. T. Kajihara, S. Tazuma, G. Yamashita, and G. Kajiyama Effects of bilirubin ditaurate on biliary secretion of proteins and lipids: influence on the hepatic vesicle transport system J Gastroenterol Hepatol 14 1999 578 582 (Pubitemid 29281881)
114. T. Kajihara, S. Tazuma, G. Yamashita, and G. Kajiyama Bilirubin overload modulates bile canalicular membrane fluidity in rats: association with disproportionate reduction of biliary lipid secretion J Gastroenterol 35 2000 450 455 (Pubitemid 30428063)
115. T. Hirohashi, H. Suzuki, K. Ito, K. Ogawa, K. Kume, and T. Shimizu Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats Mol Pharmacol 53 1998 1068 1075 (Pubitemid 28280450)
116. D.F. Ortiz, S. Li, R. Iyer, X. Zhang, P. Novikoff, and I.M. Arias MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte Am J Physiol 276 1999 G1493 G1500
117. N. Ballatori, and J.F. Rebbeor Roles of MRP2 and OATP1 in hepatocellular export of reduced glutathione Semin Liver Dis 18 1998 377 387 (Pubitemid 29011041)
118. X.Y. Chu, J.R. Strauss, M.A. Mariano, J. Li, D.J. Newton, and X. Cai Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2) J Pharmacol Exp Ther 317 2006 579 589
119. H. Naba, C. Kuwayama, C. Kakinuma, S. Ohnishi, and T. Ogihara Eisai hyperbilirubinemic rat (EHBR) as an animal model affording high drug-exposure in toxicity studies on organic anions Drug Metab Pharmacokinet 19 2004 339 351
120. H. Akita, H. Suzuki, K. Ito, S. Kinoshita, N. Sato, and H. Takikawa Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump Biochim Biophys Acta 1511 2001 7 16 (Pubitemid 32206667)
121. C. Baigent, A. Keech, P.M. Kearney, L. Blackwell, G. Buck, and C. Pollicino Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins Lancet 366 2005 1267 1278
122. J. Stamler, O. Vaccaro, J.D. Neaton, and D. Wentworth Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial Diabetes Care 16 1993 434 444 (Pubitemid 23046633)
123. P.M. Kearney, L. Blackwell, R. Collins, A. Keech, J. Simes, and R. Peto Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis Lancet 371 2008 117 125
124. M.R. Law, N.J. Wald, and A.R. Rudnicka Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis BMJ 326 2003 1423
125. L. Novotny, and L. Vitek Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies Exp Biol Med (Maywood) 228 2003 568 571 (Pubitemid 37203679)
126. M. Stoeckius, A. Erat, T. Fujikawa, M. Hiromura, A. Koulova, and L. Otterbein 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 287 2012 15418 15426
127. R. Ollinger, M. Bilban, A. Erat, A. Froio, J. McDaid, and S. Tyagi Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation Circulation 112 2005 1030 1039 (Pubitemid 41170272)
128. L. Vitek, L. Novotny, M. Sperl, R. Holaj, and J. Spacil The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis Cerebrovasc Dis 21 2006 408 414 (Pubitemid 44617309)
129. J.A. Araujo, M. Zhang, and F. Yin Heme oxygenase-1, oxidation, inflammation, and atherosclerosis Front Pharmacol 3 2012 119
130. G. Lippi, G. Targher, M. Montagnana, G.L. Salvagno, and G.C. Guidi Bilirubin concentration and cardiovascular risk profile Liver Int 29 2009 315 316
131. S. Tapan, T. Dogru, I. Tasci, C.N. Ercin, T. Ozgurtas, and M.K. Erbil Soluble CD40 ligand and soluble P-selectin levels in Gilbert's syndrome: A link to protection against atherosclerosis? Clin Biochem 42 2009 791 795