Wiersma Harmen, Gatti Alberto, Nijstad Niels, Kuipers Folkert, Tietge Uwe J F
Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Lipid Res. 2009 Aug;50(8):1571-80. doi: 10.1194/jlr.M800434-JLR200. Epub 2009 Feb 28.
High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)-mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.
高密度脂蛋白胆固醇被认为是通过I型清道夫受体（SR-BI）肝脏摄取后分泌到胆汁中的甾醇的首选来源。本研究旨在确定内皮脂肪酶（EL）介导的HDL胆固醇摄取刺激对野生型、SR-BI基因敲除和SR-BI过表达小鼠肝脏脂质代谢和胆汁胆固醇分泌的代谢影响。在每个模型中，注射表达EL的腺病毒可降低血浆HDL胆固醇（P < 0.001），而肝脏胆固醇含量增加（P < 0.05），这导致甾醇调节元件结合蛋白2（SREBP2）及其靶基因HMG-CoA还原酶和低密度脂蛋白受体的表达降低（均为P < 0.01）。胆汁胆固醇分泌依赖于肝脏SR-BI的表达，在SR-BI基因敲除小鼠中降低（P < 0.001），在肝脏SR-BI过表达后增加（P < 0.001）。然而，在每个模型中，胆固醇、胆汁酸和磷脂的胆汁分泌以及粪便胆汁酸和中性甾醇含量在EL过表达后保持不变。重要的是，在这些条件下，肝脏ABCG5/G8的表达与胆汁胆固醇分泌率无关。这些结果表明，通过过表达EL急性降低血浆HDL胆固醇水平会增加肝脏胆固醇含量，但胆汁甾醇分泌不变。相反，胆汁胆固醇分泌率与肝脏SR-BI的表达水平有关。这些数据强调了SR-BI对胆汁胆固醇分泌的重要性，可能与逆向胆固醇转运的概念相关。
