SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance

• Published in: The Journal of clinical investigation 2008-01, Vol.118 (1), p.364-375
• Main Authors: Cai, Lei, Ji, Ailing, de Beer, Frederick C, Tannock, Lisa R, van der Westhuyzen, Deneys R
• Format: Article
• Language: English
• Subjects: Adrenal Glands - metabolism; Adrenal Glands - pathology; Adrenocorticotropic Hormone - genetics; Adrenocorticotropic Hormone - metabolism; Animals; Bacterial infections; Biomedical research; Cholesterol; Cholesterol Esters - genetics; Cholesterol Esters - metabolism; Corticosteroids; Corticosterone - metabolism; Cytokines; Endotoxemia - chemically induced; Endotoxemia - genetics; Endotoxemia - metabolism; Endotoxemia - pathology; Glucocorticoids - metabolism; Gram-positive bacteria; Hepatocytes - metabolism; Hepatocytes - pathology; High density lipoprotein receptors; Infections; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Lipopolysaccharides - toxicity; Lipoproteins, HDL - genetics; Lipoproteins, HDL - metabolism; Liver - metabolism; Liver - pathology; Low density lipoprotein receptors; Mice; Mice, Knockout; Pathogens; Physiological aspects; Physiology; Plasma; Polysaccharides; Prevention; Proteins; Receptors, Lipoprotein - genetics; Receptors, Lipoprotein - metabolism; Risk factors; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Sepsis; Septic shock; Shock, Septic - chemically induced; Shock, Septic - genetics; Shock, Septic - metabolism; Shock, Septic - pathology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci31539

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.