{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:17:12Z","timestamp":1791497832266,"version":"4.3.4"},"reference-count":141,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK121797"],"award-info":[{"award-number":["R01DK121797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DA058933"],"award-info":[{"award-number":["R01DA058933"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL174521"],"award-info":[{"award-number":["R01HL174521"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F31HL170972"],"award-info":[{"award-number":["F31HL170972"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["25PRE1374495"],"award-info":[{"award-number":["25PRE1374495"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Bilirubin, a metabolite derived from heme degradation, has traditionally been regarded as a waste product and a marker of liver injury. However, increasing evidence suggests that bilirubin also functions as a hormone, and reduced levels are associated with metabolic dysfunction. Studies have shown a strong association between low circulating bilirubin levels and an increased risk of metabolic disorders and cardiovascular disease. To advance bilirubin-based treatment strategies, it is essential to elucidate the mechanisms underlying bilirubin transport and metabolism. Therefore, we provide an in-depth discussion of bilirubin production and its subsequent fates, with a particular focus on the transport between the liver and the intestine. We describe the molecular players involved in heme degradation and biliverdin formation, leading to bilirubin production, followed by its transport from the bloodstream to hepatocytes and from the liver to the intestine. We discuss intestinal bilirubin catabolism, including the microbiome generation of urobilinogen, urobilin, and other metabolites. Finally, we discuss how bilirubin clearance and catabolism intersect with its metabolic effects, highlighting potential therapeutic targets. By integrating these aspects, this review provides a comprehensive understanding of bilirubin\u2019s physiological importance, intestinal transport, and breakdown, as well as insights into novel strategies for treating hypobilirubinemia-associated disorders.<\/jats:p>","DOI":"10.3390\/antiox14111326","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T16:18:42Z","timestamp":1762186722000},"page":"1326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Bilirubin Hepatic and Intestinal Transport and Catabolism: Physiology, Pathophysiology, and Benefits"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7344-7469","authenticated-orcid":false,"given":"Zachary A.","family":"Kipp","sequence":"first","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7365-7172","authenticated-orcid":false,"given":"Sally N.","family":"Pauss","sequence":"additional","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-7708","authenticated-orcid":false,"given":"Genesee J.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7599-1529","authenticated-orcid":false,"suffix":"Jr.","given":"Terry D.","family":"Hinds","sequence":"additional","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40508, USA"},{"name":"Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA"},{"name":"Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5258-8318","authenticated-orcid":false,"given":"Wang-Hsin","family":"Lee","sequence":"additional","affiliation":[{"name":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40508, USA"},{"name":"Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.molmed.2023.01.007","article-title":"The physiology of bilirubin: Health and disease equilibrium","volume":"29","author":"Vitek","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E191","DOI":"10.1152\/ajpendo.00405.2020","article-title":"Bilirubin as a metabolic hormone: The physiological relevance of low levels","volume":"320","author":"Creeden","year":"2021","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9804","DOI":"10.1074\/jbc.RA120.013700","article-title":"Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor alpha","volume":"295","author":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1152\/physiolgenomics.00028.2019","article-title":"RNA sequencing in human HepG2 hepatocytes reveals PPAR-alpha mediates transcriptome responsiveness of bilirubin","volume":"51","author":"Gordon","year":"2019","journal-title":"Physiol. Genom."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Stec, D.E., John, K., Trabbic, C.J., Luniwal, A., Hankins, M.W., Baum, J., and Hinds, T.D. (2016). Bilirubin Binding to PPARalpha Inhibits Lipid Accumulation. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153427"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kipp, Z.A., Badmus, O.O., Stec, D.E., Hall, B., and Hinds, T.D. (2025). Bilirubin bioconversion to urobilin in the gut-liver-kidney axis: A biomarker for insulin resistance in the Cardiovascular-Kidney-Metabolic (CKM) Syndrome. Metabolism, 163.","DOI":"10.1016\/j.metabol.2024.156081"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.tem.2018.01.002","article-title":"Bilirubin in the Liver-Gut Signaling Axis","volume":"29","author":"Hamoud","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.18632\/oncotarget.12277","article-title":"Glucuronidation and UGT isozymes in bladder: New targets for the treatment of uroepithelial carcinomas?","volume":"8","author":"Sundararaghavan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0168-8278(02)00359-8","article-title":"Inherited disorders of bilirubin metabolism","volume":"38","author":"Bosma","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3727\/000000005783983250","article-title":"Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1","volume":"14","author":"Ambrosino","year":"2005","journal-title":"Cell Transpl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z","article-title":"Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype","volume":"16","author":"Kadakol","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.bpg.2010.07.007","article-title":"Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome)","volume":"24","author":"Strassburg","year":"2010","journal-title":"Best. Pract. Res. Clin. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/hep4.1660","article-title":"Rotor Syndrome: Glucuronidated Bile Acidemia From Defective Reuptake by Hepatocytes","volume":"5","author":"Kimura","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_14","first-page":"352","article-title":"Measurement and clinical usefulness of bilirubin in liver disease","volume":"2","author":"Crespo","year":"2021","journal-title":"Adv. Lab. Med.\/Av. E. Med. D Lab."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kartoun, U., Fahed, A.C., Kany, S., Singh, P., Khurshid, S., Patel, A.P., Batra, P., Philippakis, A., Khera, A.V., and Lubitz, S.A. (2023). Exploring the link between Gilbert\u2019s syndrome and atherosclerotic cardiovascular disease: Insights from a subpopulation-based analysis of over one million individuals. Eur. Heart J. Open, 3.","DOI":"10.1093\/ehjopen\/oead059"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1016\/j.jacl.2023.05.043","article-title":"Cardioprotection from a Silent Syndrome: Effect of Gilbert\u2019s Syndrome on Cardiovascular Disease in Patients with Familial Hypercholesteremia","volume":"17","author":"Brown","year":"2023","journal-title":"J. Clin. Lipidol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0021-9150(01)00601-3","article-title":"Gilbert syndrome and ischemic heart disease: A protective effect of elevated bilirubin levels","volume":"160","author":"Jirsa","year":"2002","journal-title":"Atherosclerosis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.atherosclerosis.2014.12.042","article-title":"Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert\u2019s syndrome?","volume":"239","author":"Kundur","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2008.01.001","article-title":"Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: Possible protective effects and therapeutic applications of bilirubin","volume":"198","author":"Schwertner","year":"2008","journal-title":"Atherosclerosis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H429","DOI":"10.1152\/ajpheart.00417.2017","article-title":"Bilirubin acts as a multipotent guardian of cardiovascular integrity: More than just a radical idea","volume":"315","author":"Bulmer","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1042\/CS20242825","article-title":"Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: A focus on diabetes and therapeutics","volume":"139","author":"Lee","year":"2025","journal-title":"Clin Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kipp, Z.A., Martinez, G.J., Bates, E.A., Maharramov, A.B., Flight, R.M., Moseley, H.N.B., Morris, A.J., Stec, D.E., and Hinds, T.D. (2023). Bilirubin Nanoparticle Treatment in Obese Mice Inhibits Hepatic Ceramide Production and Remodels Liver Fat Content. Metabolites, 13.","DOI":"10.3390\/metabo13020215"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kipp, Z.A., Xu, M., Bates, E.A., Lee, W.H., Kern, P.A., and Hinds, T.D. (2023). Bilirubin Levels Are Negatively Correlated with Adiposity in Obese Men and Women, and Its Catabolized Product, Urobilin, Is Positively Associated with Insulin Resistance. Antioxidants, 12.","DOI":"10.3390\/antiox12010170"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fu, J., Wang, Q., Zhang, L., Liu, J., and Wang, G. (2022). Serum Bilirubin Level Is Increased in Metabolically Healthy Obesity. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.792795"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s13098-021-00762-0","article-title":"Associations between serum total bilirubin, obesity and type 2 diabetes","volume":"13","author":"Wei","year":"2021","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Takei, R., Inoue, T., Sonoda, N., Kohjima, M., Okamoto, M., Sakamoto, R., Inoguchi, T., and Ogawa, Y. (2019). Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0223302"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liu, J., Dong, H., Zhang, Y., Cao, M., Song, L., Pan, Q., Bulmer, A., Adams, D.B., Dong, X., and Wang, H. (2016). Corrigendum: Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPAR\u03b3 Levels. Sci. Rep., 6.","DOI":"10.1038\/srep19170"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.atherosclerosis.2017.12.021","article-title":"Mild hyperbilirubinaemia as an endogenous mitigator of overweight and obesity: Implications for improved metabolic health","volume":"269","author":"Grindel","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.cmet.2013.01.005","article-title":"HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis","volume":"17","author":"White","year":"2013","journal-title":"Cell Metab."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chiabrando, D., Vinchi, F., Fiorito, V., Mercurio, S., and Tolosano, E. (2014). Heme in pathophysiology: A matter of scavenging, metabolism and trafficking across cell membranes. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00061"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.abb.2013.10.013","article-title":"Heme oxygenation and the widening paradigm of heme degradation","volume":"544","author":"Wilks","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"H2405","DOI":"10.1152\/ajpheart.2000.279.5.H2405","article-title":"Effects of hemoglobin on heme oxygenase gene expression and viability of cultured smooth muscle cells","volume":"279","author":"Marton","year":"2000","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.freeradbiomed.2018.07.018","article-title":"An intimate crosstalk between iron homeostasis and oxygen metabolism regulated by the hypoxia-inducible factors (HIFs)","volume":"133","author":"Hirota","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1073\/pnas.93.2.795","article-title":"Heme oxygenase 2: Endothelial and neuronal localization and role in endothelium-dependent relaxation","volume":"93","author":"Zakhary","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1172\/JCI106841","article-title":"Metabolic regulation of heme catabolism and bilirubin production. I. Hormonal control of hepatic heme oxygenase activity","volume":"51","author":"Bakken","year":"1972","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/S0006-291X(86)80205-4","article-title":"Characterization of two heme oxygenase isoforms in rat spleen: Comparison with the hematin-induced and constitutive isoforms of the liver","volume":"141","author":"Braggins","year":"1986","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1002\/hep.510270327","article-title":"Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver","volume":"27","author":"Bauer","year":"1998","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00795-018-0205-z","article-title":"Protective role of heme oxygenase-1 in fatty liver ischemia-reperfusion injury","volume":"52","author":"Li","year":"2019","journal-title":"Med. Mol. Morphol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S1471-4906(03)00181-9","article-title":"Heme oxygenase-1: Unleashing the protective properties of heme","volume":"24","author":"Otterbein","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.rvsc.2014.07.018","article-title":"Cellular stress marker alteration and inflammatory response in pigs fed with an ochratoxin contaminated diet","volume":"97","author":"Bernardini","year":"2014","journal-title":"Res. Vet. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/labinvest.3700691","article-title":"A novel endotoxin-induced pathway: Upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction","volume":"88","author":"Duvigneau","year":"2008","journal-title":"Lab. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1007\/s00018-016-2223-0","article-title":"Role of Nrf2\/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism","volume":"73","author":"Loboda","year":"2016","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"69075","DOI":"10.18632\/oncotarget.11923","article-title":"The non-canonical functions of the heme oxygenases","volume":"7","author":"Vanella","year":"2016","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.2174\/0929867324666170616110748","article-title":"Effects of Polyphenolic Derivatives on Heme Oxygenase-System in Metabolic Dysfunctions","volume":"25","author":"Pittala","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.4155\/fmc-2018-0448","article-title":"Synthesis, in vitro and in silico studies of HO-1 inducers and lung antifibrotic agents","volume":"11","author":"Vanella","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1124\/pr.55.3.5","article-title":"Different faces of the heme-heme oxygenase system in inflammation","volume":"55","author":"Wagener","year":"2003","journal-title":"Pharmacol. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Consoli, V., Sorrenti, V., Grosso, S., and Vanella, L. (2021). Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions. Biomolecules, 11.","DOI":"10.3390\/biom11040589"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7074","DOI":"10.1093\/nar\/gkm638","article-title":"Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1","volume":"35","author":"Reichard","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s12975-015-0433-7","article-title":"Ginkgo biloba Extract Prevents Female Mice from Ischemic Brain Damage and the Mechanism Is Independent of the HO1\/Wnt Pathway","volume":"7","author":"Tulsulkar","year":"2016","journal-title":"Transl. Stroke Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ryter, S.W. (2021). Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115509"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Williams, K.I., Suryadevara, P., Zhan, C.G., Hinds, T.D., and Kipp, Z.A. (2025). Urobilin Derived from Bilirubin Bioconversion Binds Albumin and May Interfere with Bilirubin Interacting with Albumin: Implications for Disease Pathology. Biomedicines, 13.","DOI":"10.3390\/biomedicines13020302"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Gordon, D.M., Hong, S.H., Kipp, Z.A., and Hinds, T.D. (2021). Identification of Binding Regions of Bilirubin in the Ligand-Binding Pocket of the Peroxisome Proliferator-Activated Receptor-A (PPARalpha). Molecules, 26.","DOI":"10.3390\/molecules26102975"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gu, R., Qin, F.-Y., Wang, L., Zhang, J., Emerson, J., Ma, Q., Lu, J., Anderson, K.E., Wang, J., and Ma, X. (2025). OATP1B1\/1B3 deficiency exacerbates hyperbilirubinemia in erythropoietic protoporphyria. Drug Metab. Dispos., 53.","DOI":"10.1016\/j.dmd.2025.100105"},{"key":"ref_54","first-page":"35","article-title":"A Novel Fluorescence-Based Assay for the Measurement of Biliverdin Reductase Activity","volume":"5","author":"Adeosun","year":"2018","journal-title":"React. Oxyg. Species"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.tem.2015.02.001","article-title":"Biliverdin reductase isozymes in metabolism","volume":"26","author":"Hosick","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1111\/j.1432-1033.1995.467_2.x","article-title":"Changes in the composition of bilirubin-IX isomers during human prenatal development","volume":"233","author":"Yamaguchi","year":"1995","journal-title":"Eur. J. Biochem.S"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1172\/JCI106184","article-title":"Studies of bilirubin kinetics in normal adults","volume":"48","author":"Berk","year":"1969","journal-title":"J. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1002\/jlac.198219821002","article-title":"Chromatographic-Separation and Spectroscopic Characterization of the Bilirubin Isomer-Iii-Alpha, Isomer-Ix-Alpha, Isomer-Xiii-Alpha, and Their Dimethyl Esters","volume":"1982","author":"Defoinstraatmann","year":"1982","journal-title":"Liebigs Ann. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0014-5793(71)80475-1","article-title":"Commercial bilirubin: A trinity of isomers","volume":"18","author":"McDonagh","year":"1971","journal-title":"FEBS Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1111\/j.1478-3231.2008.01716.x","article-title":"Bilirubin in clinical practice: A review","volume":"28","author":"Fevery","year":"2008","journal-title":"Liver Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1172\/JCI109797","article-title":"Mechanism of bilirubin diglucuronide formation in intact rats: Bilirubin diglucuronide formation in vivo","volume":"65","author":"Blanckaert","year":"1980","journal-title":"J. Clin. Investig."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Hinds, T.D., Creeden, J.F., Gordon, D.M., Spegele, A.C., Britton, S.L., Koch, L.G., and Stec, D.E. (2020). Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1. Antioxidants, 9.","DOI":"10.3390\/antiox9090889"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1249\/MSS.0b013e3182357dd4","article-title":"Effect of different doses of aerobic exercise training on total bilirubin levels","volume":"44","author":"Swift","year":"2012","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Flack, K.D., Vitek, L., Fry, C.S., Stec, D.E., and Hinds, T.D. (2022). Cutting edge concepts: Does bilirubin enhance exercise performance?. Front. Sports Act. Living, 4.","DOI":"10.3389\/fspor.2022.1040687"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Goluch, Z., Wierzbicka-Rucinska, A., and Ksiazek, E. (2024). Nutrition in Gilbert\u2019s Syndrome-A Systematic Review of Clinical Trials According to the PRISMA Statement. Nutrients, 16.","DOI":"10.3390\/nu16142247"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1136\/heartjnl-2019-315485","article-title":"Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease","volume":"106","author":"Smith","year":"2020","journal-title":"Heart"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S1386-6346(01)00159-0","article-title":"Expression of the hepatocyte canalicular multidrug resistance protein (MRP2) in primary biliary cirrhosis","volume":"23","author":"Baretton","year":"2002","journal-title":"Hepatol. Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Beer, A.J., Hertz, D., Seemann, E., Beretta, M., Westermann, M., Bauer, R., Bauer, M., Kessels, M.M., and Qualmann, B. (2020). Reduced Mrp2 surface availability as PI3K\u03b3-mediated hepatocytic dysfunction reflecting a hallmark of cholestasis in sepsis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-69901-3"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41564-023-01549-x","article-title":"BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen","volume":"9","author":"Hall","year":"2024","journal-title":"Nat. Microbiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.molmed.2024.12.007","article-title":"Gut microbiota and bilirubin metabolism: Unveiling new pathways in health and disease","volume":"31","author":"Vitek","year":"2025","journal-title":"Trends Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jhep.2004.10.012","article-title":"The impact of intestinal microflora on serum bilirubin levels","volume":"42","author":"Vitek","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"191","DOI":"10.5650\/jos.55.191","article-title":"Urobilinogen, as a Bile Pigment Metabolite, Has an Antioxidant Function","volume":"55","author":"Mitsuo","year":"2006","journal-title":"J. Oleo Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.trre.2018.06.003","article-title":"Bilirubin, a new therapeutic for kidney transplant?","volume":"32","author":"Sundararaghavan","year":"2018","journal-title":"Transpl. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12933-022-01484-x","article-title":"Bilirubin as an indicator of cardiometabolic health: A cross-sectional analysis in the UK Biobank","volume":"21","author":"Wagner","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/apha.12858","article-title":"Chronically elevated bilirubin protects from cardiac reperfusion injury in the male Gunn rat","volume":"220","author":"Bakrania","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.jhep.2004.12.002","article-title":"Intestinal flora and bilirubin","volume":"42","author":"Tiribelli","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1056\/NEJM196307252690402","article-title":"Intestinal absorption of bile pigments. II. Bilirubin absorption in man","volume":"269","author":"Lester","year":"1963","journal-title":"N. Engl. J. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1172\/JCI105185","article-title":"Intestinal Absorption of Bile Pigments. 3. The Enterohepatic Circulation of Urobilinogen in the Rat","volume":"44","author":"Lester","year":"1965","journal-title":"J. Clin. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/201711a0","article-title":"Enterohepatic Circulation of Urobilinogen","volume":"201","author":"Lester","year":"1964","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/oby.21724","article-title":"Metabolites distinguishing visceral fat obesity and atherogenic traits in individuals with overweight","volume":"25","author":"Baek","year":"2017","journal-title":"Obes. Silver Spring"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ottosson, F., Smith, E., Fernandez, C., and Melander, O. (2020). Plasma Metabolites Associate with All-Cause Mortality in Individuals with Type 2 Diabetes. Metabolites, 10.","DOI":"10.3390\/metabo10080315"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/ehf2.12453","article-title":"The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population","volume":"6","author":"Stenemo","year":"2019","journal-title":"ESC Heart Fail."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0016-5085(19)33498-5","article-title":"Studies on the mechanism of fasting hyperbilirubinemia","volume":"61","author":"Bloomer","year":"1971","journal-title":"Gastroenterology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S0016-5085(71)80062-8","article-title":"The effect of diet and fasting on the serum bilirubin concentration in the rat","volume":"60","author":"Barrett","year":"1971","journal-title":"Gastroenterology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1971.03190100033006","article-title":"Hyperbilirubinemia of fasting","volume":"217","author":"Barrett","year":"1971","journal-title":"JAMA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1042\/CS20257571","article-title":"The physiology of MASLD: Molecular pathways between liver and adipose tissues","volume":"139","author":"Lee","year":"2025","journal-title":"Clin. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Stelzer, T.C., Kruger, R., Ferrario, P.G., Molzer, C., Wallner, M., Marculescu, R., Doberer, D., Bulmer, A.C., and Wagner, K.H. (2025). Bilirubin Metabolism Does Not Influence Serum Bile Acid Profiles According to LC-MS: A Human Case-Control Study. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26062475"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"ElTatawy, S.S., Elmazzahy, E.A., El Shennawy, A.M., Madani, H.A., Abou Youssef, H., and Iskander, I.F. (2020). The spectrum of bilirubin neurotoxicity in term and near-term babies with hyperbilirubinemia: Does outcome improve with time?. Early Hum. Dev., 140.","DOI":"10.1016\/j.earlhumdev.2019.104909"},{"key":"ref_89","unstructured":"Reddy, D.K., and Pandey, S. (2025). Kernicterus. StatPearls, StatPearls Publishing."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1038\/s41390-024-03084-9","article-title":"Molecular events in brain bilirubin toxicity revisited","volume":"95","author":"Gazzin","year":"2024","journal-title":"Pediatr. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1126\/science.3029864","article-title":"Bilirubin is an antioxidant of possible physiological importance","volume":"235","author":"Stocker","year":"1987","journal-title":"Science"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"R81","DOI":"10.1152\/ajpregu.00057.2023","article-title":"Loss of hepatic PPARalpha in mice causes hypertension and cardiovascular disease","volume":"325","author":"Badmus","year":"2023","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.numecd.2021.01.002","article-title":"Physiologically increased total bilirubin is associated with reduced risk of first myocardial infarction: A meta-analysis and dose-response analysis","volume":"31","author":"Yao","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Wang, G., Qiao, L., Tang, Z., Zhou, S., Min, J., and Li, M. (2023). Association between bilirubin levels and risk of stroke: A systematic review and meta-analysis. BMJ Open, 13.","DOI":"10.1136\/bmjopen-2022-064433"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Zhong, Y., and Li, L. (2025). Bilirubin as a predictor of severity and adverse clinical outcomes of acute ischemic stroke: A systematic review and meta-analysis. BMC Neurol., 25.","DOI":"10.1186\/s12883-025-04168-7"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Zinellu, A., and Mangoni, A.A. (2024). The role of bilirubin as a biomarker of rheumatic diseases: A systematic review and meta-analysis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1369284"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.jhep.2014.07.028","article-title":"Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert\u2019s syndrome) and respiratory health in the 1946 British birth cohort","volume":"61","author":"Horsfall","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.crohns.2011.11.010","article-title":"A functional polymorphism in UGT1A1 related to hyperbilirubinemia is associated with a decreased risk for Crohn\u2019s disease","volume":"6","author":"Jenniskens","year":"2012","journal-title":"J. Crohns Colitis"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.jocn.2011.02.023","article-title":"Serum bilirubin concentrations and multiple sclerosis","volume":"18","author":"Peng","year":"2011","journal-title":"J. Clin. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"25179","DOI":"10.1074\/jbc.M116.731703","article-title":"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","volume":"291","author":"Hinds","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Tramutola, A., Di Domenico, F., Perluigi, M., and Barone, E. (2025). Biliverdin reductase-A is a key modulator in insulin signaling and metabolism. Trends Endocrinol. Metab., S1043z\u2013S2760.","DOI":"10.1016\/j.tem.2025.08.007"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Vasavda, C., Kothari, R., Ammal Kaidery, N., Chakraborty, S., Jamuna Tripathi, S., Dhindsa, R.S., Ricco, C., Shanmukha, S., Saberi, S., and Lefler, J.E. (2025). Biliverdin reductase A is a major determinant of protective NRF2 signaling. Proc. Natl. Acad. Sci. USA, 122.","DOI":"10.1073\/pnas.2513120122"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Chen, W., Tumanov, S., Fazakerley, D.J., Cantley, J., James, D.E., Dunn, L.L., Shaik, T., Suarna, C., and Stocker, R. (2021). Bilirubin deficiency renders mice susceptible to hepatic steatosis in the absence of insulin resistance. Redox Biol., 47.","DOI":"10.1016\/j.redox.2021.102152"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Lanzillotta, C., Tramutola, A., Lanzillotta, S., Greco, V., Pagnotta, S., Sanchini, C., Di Angelantonio, S., Forte, E., Rinaldo, S., and Paone, A. (2024). Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3beta. Redox Biol., 73.","DOI":"10.1016\/j.redox.2024.103221"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"F323","DOI":"10.1152\/ajprenal.00495.2017","article-title":"Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells","volume":"315","author":"Adeosun","year":"2018","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Gordon, D.M., Adeosun, S.O., Ngwudike, S.I., Anderson, C.D., Hall, J.E., Hinds, T.D., and Stec, D.E. (2019). CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation. Arch. Biochem. Biophys., 672.","DOI":"10.1016\/j.abb.2019.108072"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Stec, D.E., Gordon, D.M., Nestor-Kalinoski, A.L., Donald, M.C., Mitchell, Z.L., Creeden, J.F., and Hinds, T.D. (2020). Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice. Biomolecules, 10.","DOI":"10.3390\/biom10030387"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"119913","DOI":"10.1016\/j.lfs.2021.119913","article-title":"Biliverdin reductase-A protein levels are reduced in type 2 diabetes and are associated with poor glycometabolic control","volume":"284","author":"Cimini","year":"2021","journal-title":"Life Sci."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Ceccarelli, V., Barchetta, I., Cimini, F.A., Bertoccini, L., Chiappetta, C., Capoccia, D., Carletti, R., Di Cristofano, C., Silecchia, G., and Fontana, M. (2020). Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239091"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.nbd.2019.02.003","article-title":"Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer\u2019s disease","volume":"125","author":"Sharma","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1016\/j.bbadis.2019.02.021","article-title":"Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity","volume":"1865","author":"Cimini","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Canesin, G., Hejazi, S.M., Swanson, K.D., and Wegiel, B. (2020). Heme-Derived Metabolic Signals Dictate Immune Responses. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00066"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.4049\/jimmunol.1701443","article-title":"Deletion of Biliverdin Reductase A in Myeloid Cells Promotes Chemokine Expression and Chemotaxis in Part via a Complement C5a\u2014C5aR1 Pathway","volume":"202","author":"Bisht","year":"2019","journal-title":"J. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40842-023-00159-0","article-title":"The association between bilirubin levels, and the incidence of metabolic syndrome and diabetes mellitus: A systematic review and meta-analysis of cohort studies","volume":"10","author":"Nikouei","year":"2024","journal-title":"Clin. Diabetes Endocrinol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"E244","DOI":"10.1152\/ajpendo.00396.2016","article-title":"Mice with hyperbilirubinemia due to Gilbert\u2019s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha","volume":"312","author":"Hinds","year":"2017","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1017\/S0007114519001740","article-title":"Proteomics study of the effect of high-fat diet on rat liver","volume":"122","author":"Sang","year":"2019","journal-title":"Br. J. Nutr."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.apsb.2019.10.009","article-title":"Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice","volume":"10","author":"Wang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1124\/dmd.111.039925","article-title":"UDP-glucuronosyltransferase expression in mouse liver is increased in obesity- and fasting-induced steatosis","volume":"40","author":"Xu","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Bates, E.A., Kipp, Z.A., Martinez, G.J., Badmus, O.O., Soundarapandian, M.M., Foster, D., Xu, M., Creeden, J.F., Greer, J.R., and Morris, A.J. (2023). Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease. Biomolecules, 13.","DOI":"10.3390\/biom13020252"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1021\/mp4001348","article-title":"Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia","volume":"10","author":"Chang","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/cpt.269","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing","volume":"99","author":"Gammal","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1097\/FPC.0000000000000331","article-title":"PharmGKB summary: Atazanavir pathway, pharmacokinetics\/pharmacodynamics","volume":"28","author":"Alvarellos","year":"2018","journal-title":"Pharmacogenet Genom."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"12671","DOI":"10.1073\/pnas.231140698","article-title":"Mechanism of indinavir-induced hyperbilirubinemia","volume":"98","author":"Zucker","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1124\/dmd.105.005447","article-title":"In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation","volume":"33","author":"Zhang","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1067\/mjd.2002.124082","article-title":"Indirect hyperbilirubinemia caused by cyclosporine","volume":"47","author":"Jih","year":"2002","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2133\/dmpk.17.23","article-title":"The Potential for an Interaction between MRP2 (ABCC2) and Various Therapeutic Agents: Probenecid as a Candidate Inhibitor of the Biliary Excretion of Irinotecan Metabolites","volume":"17","author":"Horikawa","year":"2002","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1007\/BF02977375","article-title":"Effect of probenecid on the biliary excretion of belotecan","volume":"30","author":"Namkoong","year":"2007","journal-title":"Arch. Pharmacal Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1111\/j.1600-6143.2005.00779.x","article-title":"Cyclosporine Interacts with Mycophenolic Acid by Inhibiting the Multidrug Resistance-Associated Protein 2","volume":"5","author":"Hesselink","year":"2005","journal-title":"Am. J. Transplant."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1124\/dmd.105.006122","article-title":"Role of MRP2 in the Hepatic Disposition of Mycophenolic Acid and Its Glucuronide Metabolites: Effect of Cyclosporine","volume":"34","author":"Westley","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00280-019-03972-6","article-title":"Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1\/OAT3","volume":"85","author":"Huang","year":"2020","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.bcp.2015.03.005","article-title":"MK571 inhibits phase-2 conjugation of flavonols by Caco-2\/TC7 cells, but does not specifically inhibit their apical efflux","volume":"95","author":"Barrington","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0005-2736(99)00169-8","article-title":"Conjugate export pumps of the multidrug resistance protein (MRP) family: Localization, substrate specificity, and MRP2-mediated drug resistance","volume":"1461","author":"Nies","year":"1999","journal-title":"Biochim. Et Biophys. Acta (BBA)-Biomembr."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Hinds, T.D., Creeden, J.F., Gordon, D.M., Stec, D.F., Donald, M.C., and Stec, D.E. (2020). Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma beta-Hydroxybutyrate. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.594574"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"4704","DOI":"10.1021\/acsnano.3c06107","article-title":"Antioxidative Hyaluronic Acid-Bilirubin Nanomedicine Targeting Activated Hepatic Stellate Cells for Anti-Hepatic-Fibrosis Therapy","volume":"18","author":"Shinn","year":"2024","journal-title":"ACS Nano"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"115165","DOI":"10.1016\/j.celrep.2024.115165","article-title":"The adiponectin-PPARgamma axis in hepatic stellate cells regulates liver fibrosis","volume":"44","author":"Zhao","year":"2025","journal-title":"Cell Rep."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Lee, W.H., Bates, E.A., Kipp, Z.A., Pauss, S.N., Martinez, G.J., Blair, C.A., and Hinds, T.D. (2025). Insulin receptor responsiveness governs TGFbeta-induced hepatic stellate cell activation: Insulin resistance instigates liver fibrosis. FASEB J., 39.","DOI":"10.1096\/fj.202402169R"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Bates, E.A., Kipp, Z.A., Lee, W.H., Martinez, G.J., Weaver, L., Becker, K.N., Pauss, S.N., Creeden, J.F., Anspach, G.B., and Helsley, R.N. (2024). FOXS1 is increased in liver fibrosis and regulates TGFbeta responsiveness and proliferation pathways in human hepatic stellate cells. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.105691"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/hep.32467","article-title":"Hepatic kinome atlas: An in-depth identification of kinase pathways in liver fibrosis of humans and rodents","volume":"76","author":"Creeden","year":"2022","journal-title":"Hepatology"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Ai, W., Bae, S., Ke, Q., Su, S., Li, R., Chen, Y., Yoo, D., Lee, E., Jon, S., and Kang, P.M. (2021). Bilirubin Nanoparticles Protect Against Cardiac Ischemia\/Reperfusion Injury in Mice. J. Am. Heart Assoc., 10.","DOI":"10.1161\/JAHA.121.021212"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"18566","DOI":"10.1021\/acsanm.4c02015","article-title":"Bilirubin Nanoparticles Alleviate Sepsis-Induced Acute Lung Injury by Protecting Pulmonary Endothelia Glycocalyx and Reducing Inflammation","volume":"7","author":"Xia","year":"2024","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Pareek, S., Flegle, A.S., Boagni, D., Kim, J.Y., Yoo, D., Trujillo-Ocampo, A., Lee, S.E., Zhang, M., Jon, S., and Im, J.S. (2022). Post Transplantation Bilirubin Nanoparticles Ameliorate Murine Graft Versus Host Disease via a Reduction of Systemic and Local Inflammation. Front. 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