Inhibition of Cholesterol Synthesis by Policosanol

说明（由申请人提供）：非处方植物药和营养补充剂作为治疗慢性和急性疾病的安全有效的手段，受到公众的广泛欢迎，被广泛视为处方药的安全替代品。高胆固醇血症是一个普遍存在的问题，人们对替代药物非常感兴趣，而糖醇是从甘蔗中提取的一种相对较新的产品，作为降低血液胆固醇水平的一种手段，已经引起了相当大的关注。这项研究将探讨一种可能的机制，通过它来降低血液中的胆固醇水平。目前大多数证据表明，这种长链醇的混合物抑制或抑制HMG-CoA还原酶活性，这是胆固醇合成的调节步骤。为了验证这一假设，将在培养的肝癌细胞和全动物中评估胆甾醇对HMG-CoA还原酶活性的影响，并确定胆甾醇抑制该酶的机制。初步研究表明，胆甾醇不直接抑制HMG-CoA还原酶，表明胞内胆甾醇的激活/代谢或调节途径的激活是抑制这一关键胆固醇生成酶的必要条件。研究将验证这样的假设，即过氧化物酶体代谢的胆甾醇导致amp激酶的激活，然后通过磷酸化使HMG-CoA还原酶失活。另一种假设，即多酚被代谢成HMG-CoA还原酶的直接抑制剂，也将被测试。HMG-CoA还原酶的表达和活性以及amp激酶活性将在肝癌细胞和经胆甾醇处理的动物肝脏制剂中进行测量。最后，为了确定是否有必要对胆甾醇进行过氧化物酶体氧化，将确定胆甾醇在缺乏过氧化物酶体氧化途径的小鼠中抑制胆固醇合成的能力。这些研究应该建立一个坚实的，机制的理解，如何减少胆固醇合成和降低血胆固醇水平，并可能提供一个基础，预测如何使用这种化合物可能相互作用，无论是有利的还是不利的，用于治疗高胆固醇血症的处方药。

DESCRIPTION (provided by applicant): Over-the-counter botanicals and nutritional supplements have gained great popularity among the public as safe and effective means to treat chronic and acute diseases, and are widely viewed as safe alternatives to prescription medicines. Hypercholesterolemia is a widespread problem for which there is great interest in alternative medicines, and policosanol is a relatively new product derived from sugar cane that has gained considerable attention as a means to reduce blood cholesterol levels. This research will investigate a possible mechanism by which policosanol decreases blood cholesterol levels. Most current evidence indicates that this mixture of long-chain alcohols inhibits or suppresses HMG-CoA reductase activity, the regulatory step in cholesterol synthesis. To test this hypothesis, the effect of policosanol on HMG-CoA reductase activity will be evaluated in cultured hepatoma cells and in whole animals, and the mechanism by which policosanol inhibits this enzyme will be determined. Preliminary studies demonstrate that policosanol does not directly inhibit HMG-CoA reductase, indicating that intracellular activation/metabolism of policosanol, or the activation of a modulatory pathway, is necessary for the suppression of this key cholesterolgenic enzyme. Studies will test the hypothesis that peroxisomal metabolism of policosanol results in the activation of AMP-kinase, which then inactivates HMG-CoA reductase by phosphorylation. An alternative hypothesis, that policosanol is metabolized to a direct inhibitor of HMG-CoA reductase, will also be tested. HMG-CoA reductase expression and activity and AMP-kinase activity will be measured in hepatoma cells and in preparations from the livers of animals treated with policosanol. Finally, to determine if peroxisomal oxidation of policosanol is necessary, the ability of policosanol to inhibit cholesterol synthesis in mice that lack peroxisomal oxidation pathways will be determined. These studies should establish a solid, mechanistic understanding of how policosanol decreases cholesterol synthesis and lowers blood cholesterol levels, and may provide a basis for predicting how the use of this compound might interact, either favorably or unfavorably, with prescription Pharmaceuticals used for the treatment of hypercholesterolemia.