Wierzbicki Anthony S, Hardman Tim, Prince William T
Department of Chemical Pathology, St. Thomas' Hospital, London SE1 7EH, UK.
Curr Vasc Pharmacol. 2009 Jul;7(3):277-86. doi: 10.2174/157016109788340703.
Atherosclerosis is a leading cause of morbidity and mortality worldwide. Statins are established as first choice drugs for the management of hyperlipidaemia and cardiovascular risk. However, a residual cardiovascular risk, partially attributable to lipids, remains even after statin treatment. This risk appears to be associated with both high-density lipoprotein cholesterol and triglyceride lipid fractions. Several novel therapeutic approaches have been proposed to reduce lipid levels. Microsomal transfer protein (MTP) is involved in the assembly of very-low-density lipoprotein and chylomicron lipoprotein particles in the liver and the gut, respectively. In the preclinical setting, various agents that affect activity of MTP have shown that inhibition can result in profound reductions in blood triglycerides and cholesterol. Similarly, evidence of efficacy using the target has been confirmed in man with small molecule inhibitors and antisense oligonucleotides. Unfortunately, despite their efficacy in reducing lipids, the clinical utility of small molecule inhibitors has been restricted by their potential to induce hepatic steatosis. Continuing attempts to utilise this clinical target (to decrease cholesterol, triglycerides and weight) have involved the use of lower doses or non systemically absorbed MTP inhibitors.
动脉粥样硬化是全球发病和死亡的主要原因。他汀类药物已被确立为治疗高脂血症和心血管风险的首选药物。然而，即使在他汀类药物治疗后，仍存在部分归因于脂质的残余心血管风险。这种风险似乎与高密度脂蛋白胆固醇和甘油三酯脂质组分均有关联。已经提出了几种新的治疗方法来降低血脂水平。微粒体转移蛋白（MTP）分别参与肝脏和肠道中极低密度脂蛋白和乳糜微粒脂蛋白颗粒的组装。在临床前研究中，各种影响MTP活性的药物表明，抑制MTP可导致血液甘油三酯和胆固醇大幅降低。同样，在人体中使用小分子抑制剂和反义寡核苷酸已证实了针对该靶点的疗效证据。不幸的是，尽管小分子抑制剂在降低血脂方面有效，但其临床应用受到诱导肝脂肪变性可能性的限制。持续尝试利用这一临床靶点（降低胆固醇、甘油三酯和体重）涉及使用较低剂量或非全身吸收的MTP抑制剂。
