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Trends in Molecular Medicine Apr 2023Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent... (Review)
Review
Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.
Topics: Humans; Bilirubin; Heme Oxygenase-1; Cardiovascular Diseases; Reactive Oxygen Species
PubMed: 36828710
DOI: 10.1016/j.molmed.2023.01.007 -
Pediatric Research Mar 2016Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be... (Review)
Review
Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), (iii) bilirubin excretion into bile (Dubin-Johnson syndrome), or (iv) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy.
Topics: Animals; Bile; Bilirubin; Crigler-Najjar Syndrome; Gilbert Disease; Glucuronic Acid; Glucuronosyltransferase; Humans; Hyperbilirubinemia, Hereditary; Hyperbilirubinemia, Neonatal; Jaundice, Chronic Idiopathic; Liver
PubMed: 26595536
DOI: 10.1038/pr.2015.247 -
American Journal of Physiology.... Feb 2021Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene... (Review)
Review
Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.
Topics: Animals; Bilirubin; Energy Metabolism; Gene Expression Regulation; Gilbert Disease; Heme; Hormones; Humans; Hyperbilirubinemia; Metabolic Networks and Pathways; PPAR alpha
PubMed: 33284088
DOI: 10.1152/ajpendo.00405.2020 -
Physiological Reviews Jul 2020Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated... (Review)
Review
Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.
Topics: Bilirubin; Brain; Humans; Infant, Newborn; Intestinal Mucosa; Liver
PubMed: 32401177
DOI: 10.1152/physrev.00004.2019 -
World Journal of Gastroenterology Jun 2002In this paper, we summarize the main progresses made in our group in the field of the mechanism of pigment gallstone formation. It was found that after treatment with... (Review)
Review
In this paper, we summarize the main progresses made in our group in the field of the mechanism of pigment gallstone formation. It was found that after treatment with free radicals, bilirubin (BR) was changed into free radical itself, and a semiquinone free radical and a superoxide free radical bound with metal were recognized, which was detected by ESR (electron spin resonance). By the means of NMR (nuclear magnetic resonance) and IR (Infra-red spectra), it was postulated that bilirubin polymerized through the reaction between the vinyl group and the hydroxyl group under the attack of free radicals. It was also found that bilirubin free radical were liable to calcify in a kinetic study. Because of its chemical properties, bilirubin free radical was shown to be cytotoxic to hepatocyte, which was demonstrated based on the following facts: induction of phospholipid peroxidation (LPO), leakage of lactate dehydrogenase (LDH) and decrease of glutathione. As to the mechanism of bilirubin-induced cytotoxicity, it was postulated that the main target of bilirubin free radical was the cell membrane, including phospholipid and membrane bound proteins, especially spectrin, a content of cytoskeleton. Based on the results mentioned above, it was deduced that bilirubin free radical is the key factor that initiates and promotes the formation of pigment gallstone, which is consistent with other researches in recent years.
Topics: Bilirubin; Cholelithiasis; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Pigments, Biological
PubMed: 12046060
DOI: 10.3748/wjg.v8.i3.413 -
Stem Cell Reports Nov 2023UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia....
UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia. Animal models lack key human organic anion transporting polypeptides with distinct epigenetic control over bilirubin metabolism, necessitating a human model to interrogate the regulatory mechanism behind UGT1A1 function. Here, we use induced pluripotent stem cells to develop human liver organoids that can emulate conjugation failure phenotype. Bilirubin conjugation assays, chromatin immunoprecipitation, and transcriptome analysis elucidated the role of glucocorticoid antagonism in UGT1A1 activation. This antagonism prevents the binding of transcriptional repressor MECP2 at the expense of NRF2 with associated off-target effects. Therefore, we introduced functional GULO (L-gulonolactone oxidase) in human organoids to augment intracellular ascorbate for NRF2 reactivation. This engineered organoid conjugated more bilirubin and protected against hyperbilirubinemia when transplanted in immunosuppressed Crigler-Najjar syndrome rat model. Collectively, we demonstrate that our organoid system serves as a manipulatable model for interrogating hyperbilirubinemia and potential therapeutic development.
Topics: Humans; Animals; Rats; Bilirubin; NF-E2-Related Factor 2; Liver; Crigler-Najjar Syndrome; Hyperbilirubinemia; Glucuronosyltransferase; Pluripotent Stem Cells
PubMed: 37832542
DOI: 10.1016/j.stemcr.2023.09.006 -
Analytica Chimica Acta Jan 2024Prognosis, diagnosis, and treatment of several diseases strongly rely on the sensitive, selective, and accurate determination of specific biomarkers in relevant...
BACKGROUND
Prognosis, diagnosis, and treatment of several diseases strongly rely on the sensitive, selective, and accurate determination of specific biomarkers in relevant biological samples. Free biliverdin and free bilirubin represent important new biomarkers of oxidative stress, however, the lack of suitable analytical methods for their determination has hindered progress in biomedical and clinical research.
RESULTS
Here, we introduce a first comprehensive approach for robust and simultaneous determination of these bilins in serum using liquid chromatography - mass spectrometry (LC-MS). The developed analytical method exhibits linearity for both analytes within the concentration range of 0.5-100 nM, with limits of detection and quantitation determined at 0.1 nM and 0.5 nM, respectively. Moreover, several analytical pitfalls related to the intrinsic molecular structures of free bilirubin and free biliverdin and their trace concentration levels in biological samples are discussed here in detail for the first time. We have shown that the solubility, chemical stability, and affinity of these bilins to various materials strongly depend on the solvent, pH, and addition of stabilizing and chelating agents. Finally, the validated LC-MS method was successfully applied to the analysis of both bilins in fetus bovine serums, yielding higher free bilirubin/biliverdin ratios compared with previously reported values for human serum.
SIGNIFICANCE
Failure to recognize and address the challenges presented here often leads to substantial analytical errors and consequently biased interpretation of the obtained results. This pertains not only to LC-MS, but also to many other analytical platforms due to the compound-derived sources of error.
Topics: Humans; Biliverdine; Bilirubin; Chromatography, Liquid; Liquid Chromatography-Mass Spectrometry; Tandem Mass Spectrometry; Biomarkers
PubMed: 38182377
DOI: 10.1016/j.aca.2023.342073 -
American Journal of Physiology.... Jun 2018The buildup of fat in the liver (hepatic steatosis) is the first step in a series of incidents that may drive hepatic disease. Obesity is the leading cause of... (Review)
Review
The buildup of fat in the liver (hepatic steatosis) is the first step in a series of incidents that may drive hepatic disease. Obesity is the leading cause of nonalcoholic fatty liver disease (NAFLD), in which hepatic steatosis progresses to liver disease. Chronic alcohol exposure also induces fat accumulation in the liver and shares numerous similarities to obesity-induced NAFLD. Regardless of whether hepatic steatosis is due to obesity or long-term alcohol use, it still may lead to hepatic fibrosis, cirrhosis, or possibly hepatocellular carcinoma. The antioxidant bilirubin and the enzyme that generates it, biliverdin reductase A (BVRA), are components of the heme catabolic pathway that have been shown to reduce hepatic steatosis. This review discusses the roles for bilirubin and BVRA in the prevention of steatosis, their functions in the later stages of liver disease, and their potential therapeutic application.
Topics: Bilirubin; Disease Progression; Fatty Liver; Humans; Liver Cirrhosis; Oxidoreductases Acting on CH-CH Group Donors; Protective Agents
PubMed: 29494209
DOI: 10.1152/ajpgi.00026.2018 -
Current Opinion in Critical Care Apr 2022The 'gut-liver axis' is thought to play an important role in pathogenesis of sepsis. Despite a wealth of experimental data to support the concept of reciprocal crosstalk... (Review)
Review
PURPOSE OF REVIEW
The 'gut-liver axis' is thought to play an important role in pathogenesis of sepsis. Despite a wealth of experimental data to support the concept of reciprocal crosstalk between gut and liver through bacterial translocation and shaping of the microbiome by liver-derived molecules, for example bile acids, clinical data, and in particular diagnostic and therapeutic options, are limited.
RECENT FINDINGS
Assessment of organ failure in the current definition of sepsis is operationalized by means of the Sequential Organ Failure Assessment (SOFA) score, including exclusively bilirubin to reflect the complex functions of the liver but ignoring the gut. However, our understanding of the intestinal microbiome and how it is affected by critical illness has clearly improved. Microbiota maintain gut-barrier function and modulate the innate and adaptive immune system. The best-defined intervention affecting the gut microbiome, that is selective decontamination of the digestive tract (SDD) is clinically studied regarding prevention of nosocomial lung infection and antibiotic resistance patterns, although its impact on liver function has not been systematically evaluated in critical illness.
SUMMARY
Characterization of liver function beyond bilirubin and the microbiome can be achieved with contemporary sequencing and metabolomic techniques. Such studies are essential to understand how gut-liver crosstalk and 'dysbiosis' affect susceptibility to and outcome of sepsis.
Topics: Bilirubin; Critical Illness; Dysbiosis; Humans; Liver; Sepsis
PubMed: 35185139
DOI: 10.1097/MCC.0000000000000921 -
Trends in Endocrinology and Metabolism:... Mar 2018Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin... (Review)
Review
Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.
Topics: Animals; Bilirubin; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Liver; Signal Transduction
PubMed: 29409713
DOI: 10.1016/j.tem.2018.01.002