a School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center , Brooklyn , NY , USA.
b Department of Cell Biology , State University of New York Downstate Medical Center , Brooklyn , NY , USA.
Crit Rev Clin Lab Sci. 2017 Jan;54(1):26-48. doi: 10.1080/10408363.2016.1221883. Epub 2016 Oct 1.
Homozygous familial hypercholesterolemia (HoFH) is a polygenic disease arising from defects in the clearance of plasma low-density lipoprotein (LDL), which results in extremely elevated plasma LDL cholesterol (LDL-C) and increased risk of atherosclerosis, coronary heart disease, and premature death. Conventional lipid-lowering therapies, such as statins and ezetimibe, are ineffective at lowering plasma cholesterol to safe levels in these patients. Other therapeutic options, such as LDL apheresis and liver transplantation, are inconvenient, costly, and not readily available. Recently, lomitapide was approved by the Federal Drug Administration as an adjunct therapy for the treatment of HoFH. Lomitapide inhibits microsomal triglyceride transfer protein (MTP), reduces lipoprotein assembly and secretion, and lowers plasma cholesterol levels by over 50%. Here, we explain the steps involved in lipoprotein assembly, summarize the role of MTP in lipoprotein assembly, explore the clinical and molecular basis of HoFH, and review pre-clinical studies and clinical trials with lomitapide and other MTP inhibitors for the treatment of HoFH. In addition, ongoing research and new approaches underway for better treatment modalities are discussed.
家族性高胆固醇血症（HoFH）是一种由血浆低密度脂蛋白（LDL）清除缺陷引起的多基因疾病，导致血浆 LDL 胆固醇（LDL-C）极度升高，动脉粥样硬化、冠心病和早逝风险增加。常规降脂疗法，如他汀类药物和依折麦布，对降低这些患者的血浆胆固醇至安全水平无效。其他治疗选择，如 LDL 吸附和肝移植，不方便、昂贵且不易获得。最近，lomitapide 被美国食品和药物管理局批准作为 HoFH 的辅助治疗药物。Lomitapide 抑制微粒体甘油三酯转移蛋白（MTP），减少脂蛋白的组装和分泌，使血浆胆固醇水平降低超过 50%。在这里，我们解释脂蛋白组装涉及的步骤，总结 MTP 在脂蛋白组装中的作用，探讨 HoFH 的临床和分子基础，并综述 lomitapide 和其他 MTP 抑制剂治疗 HoFH 的临床前研究和临床试验。此外，还讨论了正在进行的研究和新的治疗方法。
