SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance.
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.
Department of Internal Medicine, Cardiovascular Research Center, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Lei
L
Cai
Ailing
A
Ji
Frederick C
FC
de Beer
Lisa R
LR
Tannock
Deneys R
DR
van der Westhuyzen
D000311:Adrenal Glands / Q000378:metabolism* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism*; D003345:Corticosterone / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005938:Glucocorticoids / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D002788:Cholesterol Esters; D005938:Glucocorticoids; C059714:HDL cholesteryl ester; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone