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Abstract
Several large population studies have demonstrated a negative correlation between
serum bilirubin levels and the development of obesity, hepatic steatosis, and cardiovascular
disease. Despite the strong correlative data demonstrating the protective role of
bilirubin, the mechanism by which bilirubin can protect against these pathologies
remains unknown. Bilirubin has long been known as a powerful antioxidant and also
has anti-inflammatory actions, each of which may contribute to the protection afforded
by increased levels. We have recently described a novel function of bilirubin as a
ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), which we
show specifically binds to the nuclear receptor. Bilirubin may function as a selective
PPAR modulator (SPPARM) to control lipid accumulation and blood glucose. However,
it is not known to what degree bilirubin activation of PPARα is responsible for the
protection afforded to reduce hepatic steatosis. We hypothesize that bilirubin, acting
as a novel SPPARM, increases hepatic fatty acid metabolism through a PPARα-dependent
mechanism which reduces hepatic lipid accumulation and protects against hepatic steatosis
and non-alcoholic fatty liver disease (NAFLD).