J3-8209 Bilirubin as a protective factor against the development of chronic degenerative diseases: serum biomarker and pharmacological modulation (Basic project ARRS)

Duration of the project:

1. 5. 2017 – 30. 4. 2020

Lead partner:

University of Ljubljana, Faculty of Medicine

Project partners:

University of Primorska, Faculty of Health Sciences
University of Nova Gorica
University of Ljubljana Faculty of Pharmacy

Principal investigator / researcher:

Assist. Prof. Lovro Žiberna (SICRIS, ResearchGate)

Team at UP FHS:

Assist. Prof. Ana Petelin (SICRIS, ResearchGate)
Assoc. Prof. Zala Jenko Pražnikar (SICRIS, ResearchGate)
Assoc. Prof. Mihaela Jurdana (SICRIS, ResearchGate)
Assoc. Prof. Maša Černelič Bizjak (SICRIS, ResearchGate)
Assist. Prof. Mojca Stubelj (SICRIS, ResearchGate)



Bilirubin is present in various chemical forms in the blood, namely, conjugated with glucuronic acid (direct bilirubin), unconjugated bound to serum albumin (indirect bilirubin) and unconjugated-unbound (free bilirubin). The bioactive form is the free bilirubin, which is not measured routinely in the clinical setting, but has been recently identified to be around 10 nM in serum. Importantly, nanomolar concentrations of bilirubin can protect cells from the 10,000-fold molar excess of oxidants when both substances are added exogenously to cell culture. This remarkable effect has been explained that bilirubin acting as antioxidant, is itself oxidized to biliverdin, and then recycled by biliverdin reductase back to bilirubin. All in all, bilirubin is an endogenous antioxidant with anti‑inflammatory and anti-thrombotic activity, and is inversely correlated with disease risk of the cardiovascular system, such as ischemic heart disease, hypertension, diabetes type II, metabolic syndrome, obesity, among others. Importantly, some positive lifestyle modifications, e.g. weight loss or cessation of smoking, lead to higher levels of serum bilirubin. We hypothesise that bilirubin has the potential to be used as a biomarker for cardiovascular pre‑disease states and that serum bilirubin levels can be modulated.

Modulation of serum bilirubin values is possible by either i) lifestyle modifications (reducing consumption of bilirubin due to decreased oxidative stress and decreased inflammation) or ii) pharmacological interventions (increasing serum bilirubin levels by increasing synthesis, decreasing metabolism and elimination, or by replacing it from albumin) , e.g. biliverdin reductase (BVR) induction, heme oxygenase-1 (HO-1) induction, UDP-glucuronosyltransferase (UGT1A1) inhibition, organic anion transporters (OATP) and bilitranslocase (BTL) inhibition, and on the level of interaction with bilirubin-albumin complex in blood serum.

The authors acknowledge the project “J3-8209 Bilirubin as a protective factor against the development of chronic degenerative diseases: serum biomarker and pharmacological modulation is finacially supported by the Slovenian Research Agency.