A protective association between
bilirubin and
atherosclerosis/
ischemic heart disease clearly exists in vivo. However, the relationship between
bilirubin and in vivo oxidative stress parameters in a clinical population remains poorly described. The aim of this study was to assess whether persons expressing
Gilbert syndrome (GS; i.e., unconjugated
hyperbilirubinemia) are protected from
thiol oxidation and to determine if this, in addition to their improved
lipoprotein profile, could explain reduced
oxidized low-density lipoprotein (
oxLDL) status in them. Forty-four matched GS and control subjects were recruited and blood was prepared for the analysis of
lipid profile and multiple plasma
antioxidants and measures of oxidative stress. GS subjects possessed elevated plasma reduced
thiol (8.03±1.09 versus 6.75±1.39 nmol/mg
protein; P<0.01) and
glutathione concentrations (12.7±2.39 versus 9.44±2.45 μM; P<0.001). Oxidative stress status (reduced:
oxidized glutathione; GSH:
GSSG) was significantly improved in GS (0.49±0.16 versus 0.32±0.12; P<0.001).
Protein carbonyl concentrations were negatively associated with
bilirubin concentrations and were significantly lower in persons with >40 μM
bilirubin versus controls (<17.1 μmol/L; P<0.05). Furthermore, absolute
oxLDL concentrations were significantly lower in GS subjects (P<0.05). Forward stepwise regression analysis revealed that
bilirubin was associated with increased GSH:
GSSG ratio and reduced
thiol concentrations, which, in addition to reduced circulating
LDL, probably decreased
oxLDL concentrations within the cohort. In addition, a marked reduction in total
cholesterol concentrations in hyperbilirubinemic Gunn rats is presented (Gunn 0.57±0.09 versus control 1.69±0.40 mmol/L; P<0.001), arguing for a novel role for
bilirubin in modulating
lipid status in vivo. These findings implicate the physiological importance of
bilirubin in protecting from
atherosclerosis by reducing
thiol and subsequent
lipoprotein oxidation, in addition to reducing circulating
LDL concentrations.