Bilirubin, a new therapeutic for kidney transplant?

Sundararaghavan, Vikram L.; Binepal, Sivjot; Stec, David E.; Sindhwani, Puneet; Hinds, Terry D.

doi:10.1016/j.trre.2018.06.003

Cited by 37 publications

(39 citation statements)

References 92 publications

(134 reference statements)

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“…In patients with Gilbert syndrome (increased serum UCB levels), serum bilirubin concentration was inversely related to the levels of oxidative stress markers [32]. Clinical research shows that elevated UCB levels can reduce the expression of pro-inflammatory cytokines and increase the body's antioxidant capacity [33]. In addition, evidence from experimental studies in vitro and in vivo strongly supports the data obtained in human studies.…”

Section: Discussionmentioning

confidence: 63%

Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang

Hao

Guo

et al. 2020

BMC Endocr Disord

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Background: Some studies have shown that a high level of bilirubin is a protective factor against metabolic syndrome (MS), while a high level of transaminase is a risk factor for MS. However, the existing results are inconsistent and few cohort studies have been published. Methods: Using an ambispective cohort study, 565 Kazakhs from Xinjiang, China were selected as the study subjects. The baseline serum bilirubin and transaminase levels of the subjects were divided into quartiles and the relationship between these values and the incidence of MS was analyzed. The definition of MS was based on the Joint Interim Statement (JIS) diagnostic criteria. Results: The average follow-up time for the subjects was 5.72 years. The cumulative incidence of MS was 36.11% (204 of the 565 subjects), and the incidence density was 63.10/1000 person-years. Multivariate Cox regression analysis showed that the levels of total bilirubin (TBIL) and indirect bilirubin (IBIL) were negatively correlated with the occurrence of MS, Compared to the lowest quartile level (Q1), the hazard ratios of MS the TBIL levels at the Q2-Q4 quartiles were: 0.47 (0.31-0.71), 0.53 (0.35-0.79), and 0.48 (0.32-0.72), respectively, while IBIL levels at the Q2-Q4 quartiles showed an MS hazard ratio of 0.48 (0.32-0.72), 0.54(0.36-0.81), and 0.52 (0.35-0.77), respectively, all at a 95% confidence level. However, no relationship was found between transaminase levels and the incidence of MS. Conclusion: Serum TBIL and IBIL levels were negatively correlated with the incidence of MS in a Kazakh population in China.

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Section: Discussionmentioning

confidence: 63%

Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang

Hao

Guo

et al. 2020

BMC Endocr Disord

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“…This was mostly reflected from the severe hyperbilirubinemia observed in the extremely rare Crigler–Najjar syndrome with levels in the 400–700 μM range, which can cause brain damage in infants [ 44 ]. The past two decades of heme oxygenase and bilirubin research has shown that bilirubin has many health benefits [ 1 , 2 , 45 ]. For instance, humans with the UGT1A1*28 Gilbert’s polymorphism that causes reduced levels of the UGT1A1 enzyme and increased plasma bilirubin levels in the 18–50 μM range [ 46 , 47 ], have been shown to have decreased incidence of cardiovascular disease [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

et al. 2020

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Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome proliferator-activated receptor-α (PPARα), a ligand-induced transcription factor, and the higher bilirubin HCR rats had significantly increased PPARα-target genes Fgf21, Abcd3, and Gys2. These are known to promote liver function and glycogen storage, which we found by Periodic acid–Schiff (PAS) staining that hepatic glycogen content was higher in the HCR versus the LCR. Our results demonstrate that exercise stimulates pathways that raise plasma bilirubin through alterations in hepatic enzymes involved in bilirubin synthesis and metabolism, improving liver function, and glycogen content. These mechanisms may explain the beneficial effects of exercise on plasma bilirubin levels and health in humans.

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“…Moreover, protection afforded by bilirubin against rejection of kidney transplantation has been demonstrated, and its antioxidant activity in preventing ischemia/reperfusion damage as well as its anti-inflammatory action that favors organ acceptance has been reviewed, highlighting the positive impact on renal hemodynamics (Sundararaghavan et al, 2018).…”

Section: Bilirubin and Ischemia/reperfusion Injurymentioning

confidence: 99%

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

2020

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Among antioxidants in the human body, bilirubin has been recognized over the past 20 years to afford protection against different chronic conditions, including inflammation and cardiovascular disease. Moderate increases in plasma concentration and cellular bilirubin generation from metabolism of heme via heme oxygenase (HMOX) in virtually all tissues can modulate endothelial and vascular function and exert antioxidant and antiinflammatory roles. This review aims to provide an up-to-date and critical overview of the molecular mechanisms by which bilirubin derived from plasma or from HMOX1 activation in vascular cells affects endothelial function. Understanding the molecular actions of bilirubin may critically improve the management not only of key cardiovascular diseases, but also provide insights into a broad spectrum of pathologies driven by endothelial dysfunction. In this context, therapeutic interventions aimed at mildly increasing serum bilirubin as well as bilirubin generated endogenously by endothelial HMOX1 should be considered.

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Bilirubin, a new therapeutic for kidney transplant?

Cited by 37 publications

References 92 publications

Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang

Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

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