Inhibition of Cholesterol Synthesis by Policosanol

普利醇对胆固醇合成的抑制

• 批准号: 7415194
• 负责人: TODD D PORTER
• 金额: $ 17.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415194
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Acute Disease; Adverse effects; Alcohols; Alternative Medicine; Animals; Attention; Blood; Botanicals; Canes; Cells; Cholesterol; Cholesterol Synthesis Inhibition; Chronic; Conflict (Psychology); Dose; Enzymes; Fatty Acids; Hepatic; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA reductase; Liver; Measures; Medicine; Metabolism; Monkeys; Mus; Oryctolagus cuniculus; Pathway interactions; Pharmacologic Substance; Phosphorylation; Preparation; RNA Interference; Rattus; Research; Solid; Sterols; Testing; Water; adenylate kinase; base; dietary supplements; hepatoma cell; hypercholesterolemia; in vivo; inhibitor/antagonist; interest; man; oxidation; policosanol; prescription document; prescription procedure; sugar

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.

描述(申请人提供)：非处方药和营养补充剂作为治疗慢性和急性疾病的安全和有效手段，在公众中广受欢迎，并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Polosol是一种从甘蔗中提取的相对较新的产品，作为一种降低血液胆固醇水平的手段得到了相当大的关注。这项研究将探讨Polosol降低血液胆固醇水平的可能机制。目前的大多数证据表明，这种长链醇的混合物抑制或抑制HMG-CoA还原酶的活性，HMG-CoA还原酶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整个动物中评估Polosol对HMG-CoA还原酶活性的影响，并确定Polosol抑制该酶的机制。初步研究表明，Polosol并不直接抑制HMG-CoA还原酶，这表明Polosol在细胞内的激活/代谢，或调节途径的激活，是抑制这一关键的胆固醇生成酶所必需的。研究将验证这一假说，即聚多糖醇的过氧化体代谢导致AMP-激酶激活，然后AMP-激酶通过磷酸化使HMG-CoA还原酶失活。另一种假说，即Polosol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用聚多糖醇处理的动物的肝脏制剂中进行测量。最后，为了确定聚己烷醇的过氧化体氧化是否有必要，将测定聚己烷醇抑制缺乏过氧化体氧化途径的小鼠的胆固醇合成的能力。这些研究应该建立一个坚实的、机械的理解，了解Polosol是如何减少胆固醇合成和降低血液胆固醇水平的，并可能为预测这种化合物的使用如何与用于治疗高胆固醇血症的处方药相互作用提供基础，无论是有利的还是不利的。