Atherosclerosis is a chronic inflammatory disease caused mainly by
lipid accumulation and excessive inflammatory immune response. Although the
lipid-lowering and cardioprotective properties of
bilirubin, as well as the negative relationship between
bilirubin and
atherosclerosis, were well documented, it is not yet clear whether
bilirubin can attenuate
atherosclerosis in vivo. In this study, we investigated the role of
bilirubin in improving
atherosclerosis. We found that mildly elevated
bilirubin significantly reduced the risk factors of
atherosclerosis, such as plasma
glucose, total
cholesterol, and
low-density lipoprotein cholesterol, and the formation of
atherosclerotic plaques, liver total
cholesterol, and
cholesterol ester concentration in
apolipoprotein E-deficient (
ApoE-/-) mice fed a western-type (high fat) diet. It was further found that
bilirubin could promote the degradation of
3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting
enzyme for endogenous
cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with
atherosclerosis risk factors and contribute to the improvement of
atherosclerosis, in
ApoE-/- mice treated with
bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total
cholesterol or
low-density lipoprotein cholesterol was detected after
bilirubin treatment. In this study, we demonstrate that
bilirubin serves as a negative regulator of
atherosclerosis and reduces
atherosclerosis by inhibiting
cholesterol synthesis and modulating the immune system.