SR-BI Protects against Endotoxemia in Mice through Its Roles in Glucocorticoid Production and Hepatic Clearance

Authors

Lei Cai, University of KentuckyFollow
Ailing Ji, University of KentuckyFollow
Frederick C. de Beer, University of KentuckyFollow
Lisa R. Tannock, University of KentuckyFollow
Deneys R. van der Westhuyzen, University of KentuckyFollow

Abstract

Septic shock results from an uncontrolled inflammatory response, mediated primarily by LPS. Cholesterol transport plays an important role in the host response to LPS, as LPS is neutralized by lipoproteins and adrenal cholesterol uptake is required for antiinflammatory glucocorticoid synthesis. In this study, we show that scavenger receptor B-I (SR-BI), an HDL receptor that mediates HDL cholesterol ester uptake into cells, is required for the normal antiinflammatory response to LPS-induced endotoxic shock. Despite elevated plasma HDL levels, SR-BI–null mice displayed an uncontrollable inflammatory cytokine response and a markedly higher lethality rate than control mice in response to LPS. In addition, SR-BI–null mice showed a lack of inducible glucocorticoid synthesis in response to LPS, bacterial infection, stress, or ACTH. Glucocorticoid insufficiency in SR-BI–null mice was due to primary adrenal malfunction resulting from deficient cholesterol delivery from HDL. Furthermore, corticosterone supplementation decreased the sensitivity of SR-BI–null mice to LPS. Plasma from control and SR-BI–null mice exhibited a similar ability to neutralize LPS, whereas SR-BI–null mice showed decreased plasma clearance of LPS into the liver and hepatocytes compared with normal mice. We conclude that SR-BI in mice is required for the antiinflammatory response to LPS-induced endotoxic shock, likely through its essential role in facilitating glucocorticoid production and LPS hepatic clearance.

Document Type

Article

Publication Date

1-2008

Notes/Citation Information

Published in The Journal of Clinical Investigation, v. 118, no. 1.

© 2007 The American Society for Clinical Investigation

The copyright holder has granted the permission for posting the article here.

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI31539

Funding Information

Funding was supported by NIH grants R01 HL63763 and P01 HL086670 (D. van der Westhuyzen) and University of Kentucky physician-scientist awards (L.R. Tannock).

Repository Citation

Cai, Lei; Ji, Ailing; de Beer, Frederick C.; Tannock, Lisa R.; and van der Westhuyzen, Deneys R., "SR-BI Protects against Endotoxemia in Mice through Its Roles in Glucocorticoid Production and Hepatic Clearance" (2008). Internal Medicine Faculty Publications. 257.
https://uknowledge.uky.edu/internalmedicine_facpub/257