Abstract

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 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 (CEs) from high-density lipoprotein for excretion via bile. In this study, we utilized AlbCreSR-BIfl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BIfl/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-BIfl/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/CE ratio in AlbCreSR-BIfl/fl mice compared to SR-BIfl/fl littermates. This disruption led to hemo- lysis and death. Notably, administering the cholesterol-lowering drug probucol normalized FC levels and the FC/CE ratio, and significantly improved survival in CLP-AlbCreSR-BIfl/fl mice. However, probucol treatment reduced survival in CLP-low- density lipoprotein receptor knockout 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.

Document Type

Article

Publication Date

2024

Notes/Citation Information

Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.jbc.2024.107974

Funding Information

This study was supported by Grants NIH R01GM121796, NIH R35GM141478, VA 1I01BX004639 and VA I01BX006408 (to X- A. Li.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or VA.

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