SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance
SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance
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DOI：
10.1172/jci31539
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
van der Westhuyzen, Deneys R.
中科院分区：
文献类型：
--
作者：
Cai, Lei;Ji, Ailing;van der Westhuyzen, Deneys R.
感染性休克是由主要由LPS介导的不受控制的炎症反应引起的。胆固醇转运在宿主对LPS的反应中起重要作用，因为LPS被脂蛋白中和，肾上腺胆固醇摄取是肾上腺糖皮质激素合成所必需的。在这项研究中，我们表明，清道夫受体B-I（SR-BI），介导的HDL胆固醇酯摄取到细胞的HDL受体，是所需的正常的LPS诱导的内毒素休克反应。尽管血浆HDL水平升高，但SR-BI-null小鼠在对LPS的响应中显示出不可控制的炎性细胞因子应答和比对照小鼠显著更高的致死率。此外，SR-BI-null小鼠显示缺乏响应于LPS、细菌感染、应激或ACTH的诱导性糖皮质激素合成。SR-BI-null小鼠中的糖皮质激素不足是由于HDL的胆固醇递送不足引起的原发性肾上腺功能障碍。此外，补充皮质酮降低SR-BI-null小鼠对LPS的敏感性。来自对照和SR-BI-null小鼠的血浆表现出类似的中和LPS的能力，而SR-BI-null小鼠与正常小鼠相比显示LPS进入肝脏和肝细胞的血浆清除率降低。我们的结论是，SR-BI在小鼠对LPS诱导的内毒素休克的抗炎反应中是必需的，可能是通过其促进糖皮质激素产生和LPS肝脏清除的重要作用。
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 andinflammatory response to LPS-induced endotoxic shock, likely through its essential role in facilitating glucocorticoid production and LPS hepatic clearance.