Wiersma Harmen, Nijstad Niels, de Boer Jan Freark, Out Ruud, Hogewerf Wytse, Van Berkel Theo J, Kuipers Folkert, Tietge Uwe J F
Center for Liver, Digestive and Metabolic Diseases, Dept. of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Atherosclerosis. 2009 Sep;206(1):141-7. doi: 10.1016/j.atherosclerosis.2009.02.022. Epub 2009 Mar 11.
The ATP Binding Cassette transporter G1 (ABCG1) has been implicated in cholesterol efflux towards HDL and reverse cholesterol transport (RCT). Biliary cholesterol secretion is considered as an important step in RCT. The aim of the present study was to determine the consequences of Abcg1 deficiency on plasma HDL, liver cholesterol metabolism and biliary cholesterol secretion under conditions of feeding either chow or a 1% cholesterol diet (HCD) or treatment with the LXR agonist T0901317.
Abcg1 expression specifically in hepatocytes is induced by both HCD (p<0.01) and T0901317 (p<0.001). HCD or T0901317 treatment resulted in significantly lower plasma HDL cholesterol levels in Abcg1 knockout mice compared with controls (p<0.05) consistent with a role of Abcg1 in cholesterol efflux towards HDL. Liver lipid composition was not affected by the absence of Abcg1. Biliary cholesterol secretion was 47% higher in Abcg1(-/-) mice on HCD (p<0.05) and not different in the chow and the T0901317 groups. The hepatic gene expression profile indicated uniformly throughout the different treatment groups decreased expression of Srebp2 and its target genes HmgCoA reductase (p<0.05) and LDL receptor (p<0.05) in Abcg1(-/-) mice.
These data demonstrate that Abcg1 (i) contributes to plasma HDL cholesterol levels under conditions of dietary and pharmacological Lxr activation and (ii) might mediate, under conditions of hepatic cholesterol loading, hepatocyte cholesterol efflux towards plasma from a pool accessible for biliary secretion resulting in increased biliary cholesterol output when Abcg1 is lacking.
三磷酸腺苷结合盒转运体G1（ABCG1）与胆固醇向高密度脂蛋白（HDL）的流出及胆固醇逆向转运（RCT）有关。胆汁胆固醇分泌被认为是RCT中的一个重要步骤。本研究的目的是确定在给予普通饲料或1%胆固醇饮食（HCD）或用肝脏X受体（LXR）激动剂T0901317治疗的条件下，Abcg1缺乏对血浆HDL、肝脏胆固醇代谢和胆汁胆固醇分泌的影响。
HCD（p<0.01）和T0901317（p<0.001）均可特异性诱导肝细胞中Abcg1的表达。与对照组相比，HCD或T0901317治疗使Abcg1基因敲除小鼠的血浆HDL胆固醇水平显著降低（p<0.05），这与Abcg1在胆固醇向HDL流出中的作用一致。肝脏脂质组成不受Abcg1缺失的影响。在HCD喂养的Abcg1（-/-）小鼠中，胆汁胆固醇分泌增加47%（p<0.05），在普通饲料组和T0901317组中无差异。肝脏基因表达谱显示，在不同治疗组中，Abcg1（-/-）小鼠中固醇调节元件结合蛋白2（Srebp2）及其靶基因3-羟基-3-甲基戊二酰辅酶A还原酶（p<0.05）和低密度脂蛋白受体（p<0.05）的表达均一致降低。
这些数据表明，Abcg1（i）在饮食和药物激活Lxr的条件下有助于血浆HDL胆固醇水平，（ii）在肝脏胆固醇负荷条件下，可能介导肝细胞胆固醇从可用于胆汁分泌的池中向血浆的流出，当缺乏Abcg1时导致胆汁胆固醇输出增加。
