Scharnagl H, Schliack M, Löser R, Nauck M, Gierens H, Jeck N, Wieland H, Gross W, März W
Department of Medicine, Divison of Clinical Chemistry, Albert Ludwigs-University, Hugstetter Strasse 55, 79106, Freiburg, Germany.
Atherosclerosis. 2000 Nov;153(1):69-80. doi: 10.1016/s0021-9150(00)00405-6.
Lifibrol (4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) is a new hypocholesterolemic compound; it effectively lowers low density lipoprotein (LDL) cholesterol. We studied the effects of lifibrol on the cholesterol metabolism of cultured cells. In the hepatoma cell line HepG2, Lifibrol decreased the formation of sterols from [14C]-acetic acid by approximately 25%. Similar to lovastatin, lifibrol had no effect on the synthesis of sterols from [14C]-mevalonic acid. Lifibrol did not inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Instead, cholesterol synthesis inhibition by lifibrol was entirely accounted for by competitive inhibition of HMG-CoA synthase. Lifibrol enhanced the cellular binding, uptake, and degradation of LDL in cultured cells in a dose dependent fashion. The stimulation of LDL receptors was significantly stronger than expected from the effect of lifibrol on sterol synthesis. In parallel, lifibrol increased the amount of immunologically detectable receptor protein. Stimulation of LDL receptor mediated endocytosis was observed both in the presence and in the absence of cholesterol-containing lipoproteins. In the absence of an extracellular source of cholesterol, both lifibrol and lovastatin induced microsomal HMG-CoA reductase. Co-incubation with LDL was sufficient to suppress the lifibrol mediated increase in reductase activity, indicating that lifibrol does not affect the production of the non-sterol derivative(s) which are thought to regulate HMG-CoA reductase activity at the post-transcriptional level. Considered together, the data suggest that the hypolipidemic action of lifibrol may, at least in part, be mediated by sterol-independent stimulation of the LDL receptor pathway. A potential advantage of lifibrol is that therapeutic concentrations do not interfere with the production of mevalonate which is required not only to synthesize sterols but also as a precursor of electron transport moieties, glycoproteins and farnesylated proteins.
利非布罗（4-（4'-叔丁基苯基）-1-（4'-羧基苯氧基）-2-丁醇）是一种新型降胆固醇化合物；它能有效降低低密度脂蛋白（LDL）胆固醇。我们研究了利非布罗对培养细胞胆固醇代谢的影响。在肝癌细胞系HepG2中，利非布罗使[14C]-乙酸生成固醇的量减少了约25%。与洛伐他汀相似，利非布罗对[14C]-甲羟戊酸合成固醇没有影响。利非布罗不抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶。相反，利非布罗对胆固醇合成的抑制完全是由对HMG-CoA合酶的竞争性抑制引起的。利非布罗以剂量依赖的方式增强培养细胞中LDL的细胞结合、摄取和降解。LDL受体的刺激作用明显强于利非布罗对固醇合成的影响所预期的程度。同时，利非布罗增加了免疫可检测的受体蛋白的量。在有和没有含胆固醇脂蛋白的情况下，均观察到利非布罗刺激LDL受体介导的内吞作用。在没有细胞外胆固醇来源的情况下，利非布罗和洛伐他汀均可诱导微粒体HMG-CoA还原酶。与LDL共同孵育足以抑制利非布罗介导地还原酶活性增加，这表明利非布罗不影响非固醇衍生物的产生，这些非固醇衍生物被认为在转录后水平调节HMG-CoA还原酶活性。综合考虑，这些数据表明利非布罗的降血脂作用可能至少部分是由对LDL受体途径的固醇非依赖性刺激介导的。利非布罗的一个潜在优势是治疗浓度不会干扰甲羟戊酸的产生，甲羟戊酸不仅是合成固醇所必需的，也是电子传递部分、糖蛋白和法尼基化蛋白的前体所需的。
