Hyperbilirubinemia Protects against Aging-Associated Inflammation and Metabolic Deterioration.

Jaroslav Zelenka,Marie Zadinová,Aleš Dvořák,Martin Haluzík,Lukáš Alán,Libor Vítek

doi:10.1155/2016/6190609

Abstract

Mild constitutive hyperbilirubinemia is associated with a reduced risk of cardiovascular diseases, diabetes, and cancer. Since these pathologies are associated with aging, inflammation, and oxidative stress, we investigated whether hyperbilirubinemia interferes with ROS homeostasis in cell cultures and with inflammation, senescence, and mitochondrial dysfunction in aged rats. Human embryonic kidney cells and rat primary fibroblasts showed a dose-dependent decrease in the ratio of oxidized/reduced glutathione, intracellular H2O2 levels, and mitochondrial ROS production, with increasing bilirubin concentrations in the culture media. Compared to their normobilirubinemic siblings, aged hyperbilirubinemic Gunn rats showed significantly smaller amounts of visceral fat, better glucose tolerance, and decreased serum levels of proinflammatory cytokines TNFα, IL-1β, and IL-18. Simultaneously, livers from Gunn rats showed decreased expression of senescence markers and cell cycle inhibitors p21 and p16. Mitochondria from aged Gunn rats showed higher respiration and lower H2O2 production compared to controls. In conclusion, we demonstrated that mildly elevated serum bilirubin is generally associated with attenuation of oxidative stress and with better anthropometric parameters, decreased inflammatory status, increased glucose tolerance, fewer signs of cellular senescence, and enhanced mitochondrial function in aged rats.

Highlights

IntroductionWhile its extreme accumulation in neonatal brain under specific pathologic conditions is responsible for oxidative stress and neurotoxicity [1], bilirubin has been increasingly recognized as a potent endogenous antioxidant [2, 3] when only mildly elevated
Bilirubin is a natural metabolic end-product of heme breakdown
Following design was used to assess the effect of bilirubin on ROS production: medium with no bilirubin added (NO), medium with 1 μM bilirubin (Bf corresponding to physiological human serum bilirubin concentrations of about 10 μM-NORM), medium with 3 μM bilirubin (Bf corresponding to ∼30 μM serum bilirubin concentrations seen in majority of Gilbert subjects, GS), and 10 μM bilirubin (Bf corresponding to ∼70 μM, which is the upper limit of bilirubin concentrations in Gilbert syndrome subjects, as well as the bilirubin concentration present in our Gunn rat strain)

Summary

Introduction

While its extreme accumulation in neonatal brain under specific pathologic conditions is responsible for oxidative stress and neurotoxicity [1], bilirubin has been increasingly recognized as a potent endogenous antioxidant [2, 3] when only mildly elevated. Clinical trials have demonstrated that mild unconjugated hyperbilirubinemia (typically present in subjects with Gilbert syndrome) is significantly associated with lower incidence of cardiovascular and pulmonary diseases, Oxidative Medicine and Cellular Longevity diabetes, metabolic syndrome, certain cancers, and even reduced overall mortality [9]. Animal studies employing congenitally hyperbilirubinemic Gunn rats with a complete deficiency of UGT1A1 showed that hyperbilirubinemia has potent anti-inflammatory [10, 11], antiproliferative [12, 13], antigenotoxic [14], antihypertensive [15, 16], and blood lipid-modulating properties [17, 18]

Methods

Results

Conclusion