Bilirubin and beyond: A review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection

Abstract

Gilbert's syndrome (GS) is characterized by a benign, mildly elevated bilirubin concentration in the blood. Recent reports show clear protection from cardiovascular disease in this population. Protection of lipids, proteins and other macromolecules from oxidation by bilirubin represents the most commonly accepted mechanism contributing to protection in this group. However, a recent meta-analysis estimated that bilirubin only accounts for ~34% of the cardioprotective effects within analysed studies. To reveal the additional contributing variables we have explored circulating cholesterol and triacylglycerol concentrations, which appear to be decreased in hyperbilirubinemic individuals/animals, and are accompanied by lower body mass index in highly powered studies. These results suggest that bilirubin could be responsible for the development of a lean and hypolipidemic state in GS. Here we also discuss the possible contributing mechanisms that might reduce circulating cholesterol and triacylglycerol concentrations in individuals with syndromes affecting bilirubin metabolism/excretion, which we hope will stimulate future research in the area. In summary, this article is the first review of lipid status in animal and human studies of hyperbilirubinemia and explores possible mechanisms that could contribute to lowering circulating lipid parameters and further explain cardiovascular protection in Gilbert's syndrome.

Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome

“…The older GS group did not differ significantly from the younger GS group in BMI; however, the older control group had a significantly higher BMI than the older GS subgroup and could be defined as being overweight (>25 kg/m 2 ), whereas the older GS subgroup was, by definition, normal (<25 kg/m 2 ). This observation is supported by other large epidemiological observations showing lower BMI in hyperbilirubinaemic subjects ( [4,28]; see [30] for review). Interestingly, in Gunn rats, a difference in body mass was only found in female rats, which is supported by recent studies in a smaller group of aged female Gunn rats [13] and cross-sectional clinical studies [29] as recently reviewed [30].…”

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

“…In mouse models, depletion of bilirubin levels has resulted in intracerebral hemorrhage,36 neuronal apoptosis,37 traumatic brain injury,38 and cerebral ischemia 39. Increased levels of bilirubin also appear to establish a lean hypolipidemic state by decreasing circulating cholesterol and triacylglycerol concentrations9 and have been found to inhibit platelet hyperreactivity and thrombosis formation via interaction with collagen and ADP receptors 10. There is even evidence that bilirubin can inhibit neointima formation after arterial injury, block proliferation and migration of human arterial smooth muscle cells,40 and promote angiogenesis 41…”

“…Bilirubin is known to have antiatherogenic properties, mediated in part by reducing oxidative stress 7, 8, 9, 10. Individuals with Gilbert syndrome have elevated levels of unconjugated bilirubin because of a defect in uridine diphosphate glucuronosyltransferase 1A1 enzyme 11.…”

Increased large VLDL and small LDL particles are related to lower bilirubin in Type 2 diabetes mellitus

“…It is obvious that the mechanisms by which bilirubin may affect lipid homeostasis remain incompletely understood. It has been proposed that bilirubin may directly affect lipid metabolism via several pathways including hepatic VLDL assembly and cholesterol synthesis, biliary cholesterol excretion and intestinal cholesterol transport [43]. Using a Mendelian randomization approach, it has been suggested that common genetic variation in UGT1A1, the gene encoding for glucoronosyl transferase which facilitates hepatic bilirubin conjugation and excretion, does not predict obesity and plasma lipid levels [20].…”