Elevated free cholesterol levels due to impaired reverse cholesterol transport are a risk factor for polymicrobial sepsis in mice.

Dysregulated lipid metabolism is commonly observed in septic patients, but how it contributes to sepsis remains largely unknown. Reverse cholesterol transport (RCT) is crucial for regulating cholesterol metabolism in circulation. During RCT, high-density lipoprotein (HDL) collects cholesterol from peripheral tissues and transports it to the liver's scavenger receptor BI (SR-BI), where SR-BI mediates the uptake of cholesteryl esters from HDL for excretion via bile. In this study, we utilized AlbCreSR-BI^fl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BI^fl/fl mice were significantly more susceptible to cecal ligation and puncture (CLP)-induced polymicrobial sepsis, with a survival rate of 14.3% compared to 80% in SR-BI^fl/fl littermates. Mechanistically, sepsis disrupted cholesterol metabolism, causing a 4.8-fold increase in free cholesterol (FC) levels and a 4-fold increase in the FC/cholesteryl ester (CE) ratio in AlbCreSR-BI^fl/fl mice compared to SR-BI^fl/fl littermates. This disruption led to hemolysis and death. Notably, administering the cholesterol-lowering drug probucol normalized FC levels and the FC/CE ratio, and significantly improved survival in CLP-AlbCreSR-BI^fl/fl mice. However, probucol treatment reduced survival in CLP-LDLR^-/- mice, which had elevated CE levels with a low FC/CE ratio. These results highlight that elevated FC levels with high FC/CE ratio are a risk factor for sepsis. Therefore, selectively targeting elevated FC levels and FC/CE ratio could be a promising therapeutic strategy for managing sepsis.