Characteristics of the heme catabolic pathway in mild unconjugated hyperbilirubinemia and their associations with inflammation and disease prevention

Christine Mölzer,Daniel Doberer,Marlies Wallner,René Zadnikar,Karl-Heinz Wagner,Rodrig Marculescu,Anela Tosevska,Carina Kern

doi:10.1038/s41598-017-00933-y

Abstract

Heme catabolism exerts physiological functions that impact health through depressing inflammation. Upon reactive pathway progression, as in Gilbert’s Syndrome (GS; UGT1A1*28 polymorphism), aggravated health effects have been determined. Based on lower inflammation and improved metabolic health reported for GS, inter-group differences in heme catabolism were explored. Therefore, a case-control study including 120 fasted, healthy, age- and gender matched subjects with/without GS, was conducted. Genetic expressions of HMOX-1 and BLVRA were measured. Additionally participants were genotyped for those polymorphisms that are known (UGT1A1*28) or likely (HMOX-1 microsatellites) to impact bilirubinemia. Intracellular interleukins (IL-6, IL-1β, TNFα), circulatory C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (Hpt) were analysed as inflammatory markers. To assess intracellular heme oxygenase 1 (HO-1) isolated PBMCs were used. In GS vs. C, inflammation markers were significantly decreased. This was supported by an altered heme catabolism, indirectly reflecting in elevated unconjugated bilirubin (UCB; main phenotypic feature of GS) and iron, decreased hemopexin (Hpx) and Hpt and in up-regulated biliverdin reductase (BLVRA) gene expressions. Moreover, HMOX (GT)n short alleles were non-significantly more prominent in female GS individuals. Herewith, we propose a concept to elucidate why GS individuals encounter lower inflammation, and are thus less prone to oxidative-stress mediated diseases.

Highlights

Chronic, oxidative stress mediated diseases including the conditions of diabetes mellitus type 2 (DM 2), cardiovascular diseases (CVD) and cancer these days represent a major burden to both health and economy
As expected and crucial in terms of the study design, significant inter-group differences were found for unconjugated bilirubin (UCB) (p 0.000) and the respective distribution of the number of TA-repeats (i.e. UGT1A1*28 polymorphism; p 0.000)
An altered heme catabolism was indirectly determined in the present study, reflecting in significantly elevated UCB and iron levels, as well as in decreased concentrations of Hpx and Hpt

Summary

Introduction

Oxidative stress mediated (inflammatory) diseases including the conditions of diabetes mellitus type 2 (DM 2), cardiovascular diseases (CVD) and cancer these days represent a major burden to both health and economy. A plethora of reports have brought the heme catabolic pathway into play to causally explain this confirmed phenomenon of disease prevention[11] and improved metabolic health in GS individuals[12] This physiological degradation process takes place in the reticulo-endothelial system of mammals, resulting in the production of unconjugated bilirubin (UCB). When heme is enzymatically degraded, involving the pathway’s rate-limiting inducible enzyme heme oxygenase 1 (HO-1; heat-shock protein family 3213), as well as biliverdin reductase (BLVRA), UCB is produced in addition to three other separate signalling molecules[14] These intermediates with antioxidant (biliverdin IXα; carbon monoxide, CO) and anti-microbial (ferrous iron, Fe2+) properties have been suggested to impact and improve inflammation[12], and act via distinct molecular targets to influence cell function[14]

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