Niemann-Pick disease type C1 (NPC1) is a rare genetic cholesterol storage disorder caused by mutations in the NPC1 gene. Mutations in this transmembrane late endosome protein lead to loss of normal cholesterol efflux from late endosomes and lysosomes. It has been shown that broad spectrum histone deacetylase inhibitors (HDACi's) such as Vorinostat correct the cholesterol accumulation phenotype in the majority of NPC1 mutants tested in cultured cells. In order to determine the optimal specificity for HDACi correction of the mutant NPC1s, we screened 76 HDACi's of varying specificity. We tested the ability of these HDACi's to correct the excess accumulation of cholesterol in patient fibroblast cells that homozygously express NPC1^I1061T, the most common mutation. We determined that inhibition of HDACs 1, 2, and 3 is important for correcting the defect, and combined inhibition of all three is needed to achieve the greatest effect, suggesting a need for multiple effects of the HDACi treatments. Identifying the specific HDACs involved in the process of regulating cholesterol trafficking in NPC1 will help to focus the search for more specific druggable targets.

中文翻译：

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抑制组蛋白脱乙酰酶 1、2 和 3 可增强 Niemann-Pick C1 成纤维细胞中胆固醇积累的清除

Niemann-Pick 病 C1 型 (NPC1) 是一种罕见的遗传性胆固醇贮积症，由NPC1基因突变引起。这种跨膜晚期内体蛋白的突变导致晚期内体和溶酶体正常胆固醇流出的损失。已经表明，广谱组蛋白去乙酰化酶抑制剂 (HDACi's) 如伏立诺他可纠正在培养细胞中测试的大多数 NPC1 突变体中的胆固醇积累表型。为了确定突变 NPC1 的 HDACi 校正的最佳特异性，我们筛选了 76 个不同特异性的 HDACi。我们测试了这些 HDACi 纠正纯合表达NPC1 ^{I1061T的患者成纤维细胞中胆固醇过量积累的能力}，最常见的突变。我们确定抑制 HDACs 1、2 和 3 对于纠正缺陷很重要，并且需要联合抑制所有三种以达到最大效果，这表明需要 HDACi 治疗的多种效果。确定参与调节 NPC1 中胆固醇贩运过程的特定 HDAC 将有助于集中寻找更具体的药物靶点。