SUPPRESSION OF APOLIPOPROTEIN-B PRODUCTION DURING TREATMENT OF CHOLESTERYL ESTER STORAGE DISEASE WITH LOVASTATIN - IMPLICATIONS FOR REGULATION OF APOLIPOPROTEIN-B SYNTHESIS
SUPPRESSION OF APOLIPOPROTEIN-B PRODUCTION DURING TREATMENT OF CHOLESTERYL ESTER STORAGE DISEASE WITH LOVASTATIN - IMPLICATIONS FOR REGULATION OF APOLIPOPROTEIN-B SYNTHESIS
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DOI：
10.1172/jci113259
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发表时间：
1987-12-01
影响因子：
15.9
通讯作者：
DESNICK, RJ
中科院分区：
文献类型：
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作者：
GINSBERG, HN;LE, NA;DESNICK, RJ
胆固醇酯储存病（CESD）的特征是溶酶体胆固醇酯（CE）水解酶活性不足，溶酶体中ldl来源的CE积累和高脂血症。我们研究了VLDL和LDL载脂蛋白B （apoB）的动力学，使用125I-VLDL和131I-LDL，在9岁患有CESD的女性中，总胆固醇（TC） （271.0.+- 0.4.4 mg/dl），甘油三酯（TG） （150.0.+- 0.7.8 mg/dl）和LDL胆固醇（184.7.+- 0.3.4 mg/dl）升高。这些研究表明，载脂蛋白ob的产生率（PR）显著升高，主要是在LDL中，而载脂蛋白ob在VLDL和LDL中的部分分解代谢正常。尿甲羟戊酸水平升高，表明内源性胆固醇合成增加。洛伐他汀（一种羟甲基戊二酰辅酶a还原酶的竞争性抑制剂）治疗可显著降低TC （196.8.+- 0.7.9 mg/dl）、TG （100.8.+- 0.20.6 mg/dl）和LDL胆固醇（102.0.+- 0.10.9 mg/dl）。治疗降低了VLDL apoB PR （5.2 vs. 12.2 mg/kg / d预处理）和LDL apoB PR （12.7 vs. 24.2 mg/kg / d预处理）。治疗期间尿甲羟戊酸水平也有所下降。这些结果表明，在CESD中，不能从溶酶体CE释放游离胆固醇导致内源性胆固醇合成升高和含载脂蛋白的脂蛋白产生增加。洛伐他汀降低了胆固醇合成的速率和含载脂蛋白的脂蛋白的分泌。
Cholesteryl ester storage disease (CESD) is characterized by the deficient activity of lysosomal cholesteryl ester (CE) hydrolase, accumulation of LDL-derived CE in lysosomes, and hyperlipidemia. We studied the kinetics of VLDL and LDL apolipoprotein B (apoB), using 125I-VLDL and 131I-LDL, in a 9-yr-old female with CESD and elevated total cholesterol (TC) (271.0.+-.4.4 mg/dl), triglyceride (TG) (150.0.+-.7.8 mg/dl),and LDL cholesterol (184.7.+-.3.4 mg/dl). These studies demonstrated a markedly elevated production rate (PR) of apoB, primarily in LDL, with normal fractional catabolism of apoB in VLDL and LDL. Urine mevalonate levels were elevated, indicative of increased synthesis of endogenous cholesterol. Treatment with lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, resulted in significant reductions in TC (196.8.+-.7.9 mg/dl),TG (100.8.+-.20.6 mg/dl), and LDL cholesterol (102.0.+-.10.9 mg/dl). Therapy reduced VLDL apoB PR (5.2 vs. 12.2 mg/kg per d preteratment) and LDL apoB PR (12.7 vs. 24.2 mg/kg per d pretreatment). Urine mevalonate levels also decreased during therapy. These results indicate that, in CESD, the inability to release free cholesterol from lysosomal CE resulted in elevated synthesis of endogenous cholesterol and increased production of apoB-containing lipoproteins. Lovastatin reduced both the rate of cholesterol synthesis and the secretion of apoB-containing lipoproteins.