Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system

Abstract

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.

Heterogeneity of macrophages in atherosclerosis revealed by single‐cell RNA sequencing

“…4,5 The plaque microenvironment contains pro-inflammatory cytokines, oxidized lipids, cholesterol crystals, oxidative stress markers, and dangerassociated molecular patterns that trigger macrophage activation. 6,7 Macrophages perform a wide range of functions, ranging from phagocytosing apoptotic cells and pathogens to releasing immune effector molecules. Stimulation from the environment can influence macrophage phenotypes and cause them to change their function.…”

“…The immune system plays a crucial role in the development and progression of atherosclerotic lesions 4,5 . The plaque microenvironment contains pro‐inflammatory cytokines, oxidized lipids, cholesterol crystals, oxidative stress markers, and danger‐associated molecular patterns that trigger macrophage activation 6,7 . Macrophages perform a wide range of functions, ranging from phagocytosing apoptotic cells and pathogens to releasing immune effector molecules.…”

Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency

“…9 Moreover, bilirubin decreases the hepatic expression of 3-hydroxy-3-methylglutaryl-CoA reductase in Apoe −/− mice, in association with inhibition of cholesterol synthesis and a decrease in circulating cholesterol, fatty liver formation, and atherogenesis. 34 However, that study examined the effect of bilirubin on atherosclerosis lesion size, whereas the present article focuses on the effect of the bile pigment on atherosclerotic plaque composition and stability.…”

Association of Serum Bilirubin Levels with Macro- and Microvascular Complications in Chinese People with Type 2 Diabetes Mellitus: New Insight on Gender Differences

“…Bilirubin possessed antioxidant and anti-inflammatory activities, reported to attenuate atherosclerosis in vivo. 16 Atherosclerosis is the pathological basis for cardiovascular disease (CVD). 17 A cross-sectional study analyzed 1156 symptomatic intracranial atherosclerotic stenoses patients.…”