Lysosomal Acid Lipase Deficiency Impairs Regulation of ABCA1 Gene and Formation of High Density Lipoproteins in Cholesteryl Ester Storage Disease
Lysosomal Acid Lipase Deficiency Impairs Regulation of ABCA1 Gene and Formation of High Density Lipoproteins in Cholesteryl Ester Storage Disease
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DOI：
10.1074/jbc.m111.274381
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发表时间：
2011-09-02
影响因子：
4.8
通讯作者：
Francis, Gordon A.
中科院分区：
文献类型：
--
作者：
Bowden, Kristin L.;Bilbey, Nicolas J.;Francis, Gordon A.
三磷酸腺苷结合盒转运体A1(ABCA1)介导高密度脂蛋白颗粒形成的限速步骤，其表达主要通过依赖氧固醇激活肝脏X受体来调节。我们之前曾报道，溶酶体胆固醇储存障碍C1型尼曼-皮克病患者ABCA1表达和高密度脂蛋白形成受损，大多数C型尼曼-皮克病患者血浆高密度脂蛋白胆固醇水平较低。在这里，我们发现ABCA1的调节和活性在胆固醇酯储存疾病(CESD)中也受到损害，该疾病是由于LIPA基因突变导致正常溶酶体酸性脂肪酶(LAL)活性低于5%而引起的。CESD患者成纤维细胞对低密度脂蛋白(LDL)负荷的反应表现为ABCA1上调受损，磷脂和胆固醇外流到载脂蛋白A-I的减少，以及α-高密度脂蛋白颗粒的形成。用氯喹抑制LAL活性的正常成纤维细胞，ABCA1的表达和活性降低，与CESD细胞相似。肝X受体激动剂处理CESD细胞可纠正ABCA1的表达，但不能纠正低密度脂蛋白胆固醇酯的水解和胆固醇向载脂蛋白A-I的外流。与正常成纤维细胞相比，低密度脂蛋白诱导的27-羟基胆固醇的产生减少。用含有正常成纤维细胞的LAL的条件培养液或重组人LAL处理CESD细胞，可以挽救ABCA1的表达、apoA-I介导的胆固醇外流、高密度脂蛋白颗粒的形成和27-羟基胆固醇的产生。这些结果进一步证明，晚期内体/溶酶体释放胆固醇的速度是ABCA1表达和活性的关键调节因素，并解释了CESD患者出现低脂蛋白血症的原因。
ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced alpha-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.