Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents. Similar findings are reported by other groups correcting for potential cofounders, including age, sex, body mass index (BMI), smoking status, and alcohol use (84, 85). Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study. Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis. Andersson C, Weeke P, Fosbol EL, Brendorp B, Kober L, Coutinho W, Sharma AM, Van Gaal L, Finer N, James WP, Caterson ID, Rode RA, Torp-Pedersen C; SCOUT Executive Steering Committee; SCOUT investigators. The antioxidant capacity of bilirubin contributes only partially to this effect. At these elevated concentrations, bilirubin accumulation in the central nervous system can induce neurological conditions. Like many hormones, bilirubin travels through the circulatory system and reaches its target inside cells, primarily PPAR, to elicit gene responses. Despite the strong correlative evidence for a protective role of bilirubin against diabetes-induced kidney disease, the mechanism by which bilirubin can protect the kidney requires further investigation. Inherited disorders of bilirubin clearance, Hyperbilirubinemia syndromes (GilbertMeulengracht, CriglerNajjar, DubinJohnson, and Rotor syndrome). Girer NG, Murray IA, Omiecinski CJ, Perdew GH. Together, these lower the number of intracellular lipids by -oxidation of fatty acids. ), the National Heart, Lung and Blood Institute K01HL125445 (to T.D.H.) 1, and Roy Schneider at the University of Toledo College of Medicine for the graphic abstract illustration. Serum bilirubin concentration in patients with an established coronary artery disease. Double helices are DNA, and the arrow indicates PPAR target genes. Seventy-one patients diagnosed with CD and 125 sex- and age-matched healthy individuals were retrospectively analyzed during the same period. Herein, we discuss bilirubin generation, signaling as a ligand, mechanistic actions as a hormone, and how low levels may also be pathological. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase, The binding of bilirubin to serum proteins, Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions. Total Bilirubin in Prognosis for Mortality in EndStage Renal Disease 2) (14). Furthermore, the degree to which these presumably protective bilirubin increases are inhibited significantly correlate with the time patients spent <90% arterial O2 saturation (r=0.44; P value=0.04) and time spent below 85% arterial O2 saturation (r=0.49; P value=0.02) (160). Albumin-bilirubin (ALBI) showed its prognostic and predictive value in hepatobiliary disease like hepatocellular carcinoma. Levels of serum bilirubin in small cell lung cancer and non-small cell lung cancer patients. Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-A (BVRA) and suppression of UGT1A1. We found that overall high levels of bilirubin had no association with overall cancer risk. It follows that increased bilirubin concentrations (UCB) would result in increased expression of UGT and increased breakdown of carcinogens that contribute to bladder cancer development, but this is yet to be tested. Hamoud AR, Weaver L, Stec DE, Hinds TD Jr.. Bilirubin in the Liver-Gut Signaling Axis. Does bilirubin prevent hepatic steatosis through activation of the PPARalpha nuclear receptor? Bilirubin as a predictor of diseases of civilization. There are several potential mechanisms by which bilirubin can preserve renal function in hypertension, including increased nitric oxide bioavailability through bilirubins effects on superoxide production, thus reducing the formation of peroxynitrite (137, 166, 167). Silver spheres with a yellow haze in the nucleus represent bilirubin-bound PPAR in the lean, and black spheres with a blue haze are inactive PPAR in the obese. Hypothetical representation of bilirubin levels in civilization. The ordinate represents the number of patients. CA19-9>219.4 increased the risk of patient mortality by 1.70 times (95% CI 1.217-2.377, p = 0.002), and tumor poor differentiation raised the risk by 1.66 times (95% CI 1.083-2.553, P = 0.02). These findings indicate that there may be other protein signaling constituents that are lessor targets of bilirubin, such as AHR, which might occur at very high concentrations, but these are yet to be thoroughly tested. In other contexts, bilirubin acts to curb dangerous hyperinflammatory reactions resulting from pathogenic infection. The liver absorbs and uses bilirubin. The glucocorticoid receptor: cause of or cure for obesity? Puri K, Nobili V, Melville K, Corte CD, Sartorelli MR, Lopez R, Feldstein AE, Alkhouri N. Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children. identified low albumin . Researchers have determined that low-bilirubin groups present significantly increased odds for developing the metabolic syndrome (83). biliverdin reductase activity. Stec DE, Gordon DM, Hipp JA, Hong S, Mitchell ZL, Franco NR, Robison JW, Anderson CD, Stec DF, Hinds TD Jr.. Loss of hepatic PPARalpha promotes inflammation and serum hyperlipidemia in diet-induced obesity. An Oncologist Explains "Routine" Blood Tests Performed in Cancer Patients. (138) takes this mechanistic exploration further, employing in vitro studies that demonstrate normal physiological concentrations of bilirubin (1.71 to 20.52M) inhibit NF-B signaling pathways and mitigate LPS-induced sepsis in mice. The important role of bilirubin in kidney function and the regulation of blood pressure was first derived from studies in the hyperbilirubinemic Gunn rat, which demonstrated that these rats were protected against several forms of hypertension (162, 163). The function of bilirubin as a protectant of metabolic derangement is a relatively new concept that reinforces its utility as a potential antiobesity agent. New, emerging evidence suggests that low plasma bilirubin levels also predict pathology. A better understanding of bilirubins hormonal function may explain why hypobilirubinemia might be deleterious. Yang L, Ge LY, Yu T, Liang Y, Yin Y, Chen H. The prognostic impact of serum bilirubin in stage IV colorectal cancer patients, Significance and prognostic value of increased serum direct bilirubin level for lymph node metastasis in Chinese rectal cancer patients. Pancreatic tissue infiltration and islet cell inflammation in type 2 diabetes relate to the insulin resistance and cell dysfunction that drive major components of diabetic pathology (110). CA19-9 levels are higher in hyperbilirubinemia patients, resulting in a lower specificity of CA19-9 in predicting patients' survival. Together, these areas and their corresponding ranges represent hypobilirubinemic states and potential health concerns. Liu X, Meng QH, Ye Y, Hildebrandt MA, Gu J, Wu X. Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer. Obstructive cause: Management of obstructive hyperbilirubinaemia is by placement of a stent. We have long championed bilirubins functionality as an endocrine hormone; our laboratory previously published data demonstrating bilirubin-mediated activation of PPAR and its effect on downstream transcriptional activity (4, 19). Prognostic value of preoperative serum bilirubin levels in ovarian cancer Administration of bilirubin (10M) to LS174T colorectal models of ER stress resulted in decreased levels of the inflammatory and ER stress biomarkers such as TNF, IL-1, IL-8, and IL-4 (104). Memon N, Weinberger BI, Hegyi T, Aleksunes LM. The relationship between severe hyperbilirubinemia and human disease is well established. Administered as an anti-cancer therapeutic, bilirubin inhibits cancer cell growth, decreases mitochondrial function, and increases apoptosis in gastric adenocarcinoma cells (156). Notably, this activity increases when experimental conditions move from atmospheric oxygen concentrations (20%) toward concentrations found in tissues (2%) (20). official website and that any information you provide is encrypted PPARalpha-dependent induction of the energy homeostasis-regulating nuclear receptor NR1i3 (CAR) in rat hepatocytes: potential role in starvation adaptation, Intestinal Integrity, the Microbiome, and Inflammation. Biliverdin (BV) conversion by biliverdin reductase A (BVRA) to bilirubin or delivery of bilirubin nanoparticles (BRNP) activates peroxisome proliferator-activated receptor alpha (PPAR). Although patients with obstructive sleep-apnea hypopnea syndrome demonstrate increases in total bilirubin concentrations during sleep, nasal continuous positive airway pressure (CPAP) therapy significantly inhibits these bilirubin elevations (160). Mice with increased bilirubin levels due to HO-1 induction demonstrated a subsequent increase in cAMP (107), which is associated with decreased ROS generation (113). Although total serum bilirubin concentration is negatively associated with cerebral atherosclerosis, bilirubin levels are not significantly associated with cerebral small vessel disease (73). Sun H, He B, Nie Z, Pan Y, Lin K, Peng H, Xu T, Chen X, Hu X, Wu Z, Wu D, Wang S. A nomogram based on serum bilirubin and albumin levels predicts survival in gastric cancer patients, Direct bilirubin levels are prognostic in non-small cell lung cancer. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Witek K, cisowska J, Turowski D, Lerczak K, Lewandowska-Pachecka S, Pokrywka A. When bilirubin levels fall, hypobilirubinemia may increase long-term adverse clinical outcomes (Fig. Furthermore, recent evidence suggests that elevated bilirubin levels in some may not be causally associated with decreased risk of NAFLD (125). Although it has been understood for over a half-century that bilirubin binds to albumin for transport through the vascular system (26) and, since 1969, that bilirubin binds fatty acid binding protein-1 (FABP1), which is a transporter within hepatocytes (27), neither of these nor any other protein that has been reported to bind, such as ligandin, indicates a hormonal function for bilirubin, as there is no receptor target that induces a response. This may explain, in part, why bilirubin was historically considered to be a simple waste product rather than a physiologically significant antioxidant that is relevant to many common clinical pathologies. Conversion of biliverdin to bilirubin by biliverdin reductase contributes to endothelial cell protection by heme oxygenase-1-evidence for direct and indirect antioxidant actions of bilirubin. Current definitions of low bilirubin vary, but reference ranges <10M in males and <8M in females are generally cited (81). Approximately 1 in 3 people with Gilbert's syndrome don't have symptoms. The https:// ensures that you are connecting to the Bilirubin also inhibits hepatitis C viral protease activity (130). Gibbs PE, Miralem T, Lerner-Marmarosh N, Maines MD. Xi XX, Wang HL, Chen T, Dai JR, Hou SY, Chen YG. This result suggests that bilirubin protects against stroke of atherogenic origin, perhaps by way of its hormonal activity via PPAR in the vasculature, but this is yet to be tested. Like many hormones, bilirubin relies upon circulation in vascular compartments to reach its target organs. It should be noted that conjugated bilirubin has not been shown to interact with PPAR. These actions redefine bilirubin as a hormone. Yellow hexagons represent bilirubin. Earlier reports from the late 1990s suggest that bilirubin may also activate the Aryl hydrocarbon receptor (AHR) (31, 32). While investigating the mechanism behind bilirubins cardiovascular protection, researchers discovered altered lipid metabolism associated with elevated bilirubin concentrations. Wallner M, Marculescu R, Doberer D, Wolzt M, Wagner O, Vitek L, Bulmer AC, Wagner KH. 3) (25), with many patients requiring immediate liver transplantation to avoid death. Also, AHR inhibits FGF21 expression (39), whereas in several studies, bilirubin has been shown to increase levels in mice (17, 19, 40, 41), and this is a well-known PPAR target gene (35). Biliverdin is then reduced to bilirubin by the biliverdin reductase (BVR) enzyme. Serum bilirubin may have a beneficial efect on the risk of some. PPAR is the target of many diabetes medications such as the oral hypoglycemics rosiglitazone and pioglitazone. Below we discuss evidence suggesting low bilirubin serum concentrations also seem to predict significant risk stratification in patients who appear otherwise healthy. The typical range for total bilirubin is usually 0.1-1.2 milligrams per deciliter (mg/dL). Once it breaks down, it's sent through your liver, gallbladder, and. The mechanisms by which bilirubin protects against cerebrovascular disease or neuropathology remain unclear, but collective evidence suggests low levels of bilirubin may be detrimental to normal human brain physiology. Your health care provider may suspect Gilbert syndrome if you have unexplained jaundice or if the level of bilirubin is elevated in your blood. Li Y, Huang B, Ye T, Wang Y, Xia D, Qian J. Physiological concentrations of bilirubin control inflammatory response by inhibiting NF-kappaB and inflammasome activation. Clinical characteristics and laboratory parameters were analyzed in CD patients and healthy control groups. Zhang MM, Gao Y, Zheng YY, Chen Y, Liu F, Ma YT, Xie X. Outlook What is bilirubin? Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats. CRISPR-mediated knockout of BVRA in murine hepatocytes induces oxidative stress and lipid accumulation (122). Ahn KH, Kim SS, Kim WJ, Kim JH, Nam YJ, Park SB, Jeon YK, Kim BH, Kim IJ, Kim YK. ), also called a clinical stage. Although bilirubin may have unknown actions that activate other pathways, these two proteins are the only ones shown that bilirubin directly binds as a ligand agonist. Changes in blood morphology and chosen biochemical parameters in ultra-marathon runners during a 100-km run in relation to the age and speed of runners. The authors thank Matthew Hazzard at the University of Kentucky College of Medicine for the graphical illustration in Fig. Stec DE, Gordon DM, Nestor-Kalinoski AL, Donald MC, Mitchell ZL, Creeden JF, Hinds TD Jr.. Biliverdin reductase A (BVRA) knockout in adipocytes induces hypertrophy and reduces mitochondria in white fat of obese mice. Indeed, elevated serum bilirubin concentration is inversely correlated with NAFLD (116, 117). Friedlander AH, Bostrom KI, Tran HA, Chang TI, Polanco JC, Lee UK. Then, within the cell, bilirubin binds PPAR, causing a shift in corepressor proteins to coactivators to activate transcriptional control of genes. Jaundice can turn your skin and whites of the eyes yellow . Bilirubin is a promising prognostic factor for non-liver disease-related deaths in various cancers. However, the ability of bilirubin to lower blood pressure is not fully dependent on its antioxidant actions, as bilirubin is able to normalize blood pressure in angiotensin II-dependent hypertensive mice to a greater degree than treatment with the NADPH oxidase inhibitor, apocynin (168). Serum bilirubin may have a beneficial effect on the risk of some types of cancers. When diet-induced obese mice were exposed to twice-daily administration of 20M bilirubin per kilogram, the treatment group exhibited amelioration of adipose and hepatic increases in TNF and IL-1 (P < 0.05), as well as Bip and Chop (P < 0.05) (106). Prognostic value of preoperative serum bilirubin levels in ovarian cancer. By graphing a hypothetical distribution of patient serum bilirubin concentrations in Fig. Total bilirubin levels were linearly associated with the higher risk of all-cause mortality (Figure 2A; p for non-linearity = 0.118). This work was supported by the National Institutes of Health 1R01DK121797 (to T.D.H.) Bilirubin pathway and diseases associated with hypobilirubinemia. In viral infections such as HIV, bilirubin inhibits viral protease activity (129). Kim JY, Lee DY, Kang S, Miao W, Kim H, Lee Y, Jon S. Bilirubin nanoparticle preconditioning protects against hepatic ischemia-reperfusion injury.
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