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单乳糖附加β-环糊精对尼曼-匹克C型病样HepG2细胞的降胆固醇作用

Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann-Pick type C disease-like HepG2 cells.

作者信息

Motoyama Keiichi, Hirai Yumi, Nishiyama Rena, Maeda Yuki, Higashi Taishi, Ishitsuka Yoichi, Kondo Yuki, Irie Tetsumi, Era Takumi, Arima Hidetoshi

机构信息

Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan ; Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

出版信息

Beilstein J Org Chem. 2015 Nov 3;11:2079-86. doi: 10.3762/bjoc.11.224. eCollection 2015.

DOI:10.3762/bjoc.11.224
PMID:26664628
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4660966/
Abstract

The Niemann-Pick type C disease (NPC) is one of inherited lysosomal storage disorders, emerges the accumulation of unesterified cholesterol in endolysosomes. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has been applied for the treatment of NPC. HP-β-CyD improved hepatosplenomegaly in NPC patients, however, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by actively targeted-β-CyD to hepatocytes is expected. In the present study, to deliver β-CyD selectively to hepatocytes, we newly fabricated mono-lactose-appended β-CyD (Lac-β-CyD) and evaluated its cholesterol lowering effects in NPC-like HepG2 cells, cholesterol accumulated HepG2 cells induced by treatment with U18666A. Lac-β-CyD (degree of substitution of lactose (DSL) 1) significantly decreased the intracellular cholesterol content in a concentration-dependent manner. TRITC-Lac-β-CyD was associated with NPC-like HepG2 cells higher than TRITC-β-CyD. In addition, TRITC-Lac-β-CyD was partially localized with endolysosomes after endocytosis. Thus, Lac-β-CyD entered NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis and decreased the accumulation of intracellular cholesterol in NPC-like HepG2 cells. These results suggest that Lac-β-CyD may have the potential as a drug for the treatment of hepatosplenomegaly in NPC disease.

摘要

尼曼-匹克C型病（NPC）是一种遗传性溶酶体贮积症，会导致未酯化胆固醇在内溶酶体中蓄积。目前，2-羟丙基-β-环糊精（HP-β-CyD）已被用于治疗NPC。HP-β-CyD改善了NPC患者的肝脾肿大，然而，需要高剂量的HP-β-CyD。因此，期望通过将β-环糊精主动靶向肝细胞来降低剂量。在本研究中，为了将β-环糊精选择性地递送至肝细胞，我们新制备了单乳糖附加β-环糊精（Lac-β-CyD），并评估了其在NPC样HepG2细胞（用U18666A处理诱导胆固醇蓄积的HepG2细胞）中的降胆固醇作用。Lac-β-CyD（乳糖取代度（DSL）为1）以浓度依赖的方式显著降低了细胞内胆固醇含量。TRITC-Lac-β-CyD与NPC样HepG2细胞的结合高于TRITC-β-CyD。此外，TRITC-Lac-β-CyD在胞吞作用后部分定位于内溶酶体。因此，Lac-β-CyD通过去唾液酸糖蛋白受体（ASGPR）介导的胞吞作用进入NPC样HepG2细胞，并降低了NPC样HepG2细胞内胆固醇的蓄积。这些结果表明，Lac-β-CyD可能具有作为治疗NPC病肝脾肿大药物的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/c179d0be0b3e/Beilstein_J_Org_Chem-11-2079-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/1f9d5fb1c397/Beilstein_J_Org_Chem-11-2079-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/fc80bef82e48/Beilstein_J_Org_Chem-11-2079-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/ec4e5c5ae657/Beilstein_J_Org_Chem-11-2079-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/638cfeab5d4b/Beilstein_J_Org_Chem-11-2079-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/879c6b157d7d/Beilstein_J_Org_Chem-11-2079-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/c179d0be0b3e/Beilstein_J_Org_Chem-11-2079-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/1f9d5fb1c397/Beilstein_J_Org_Chem-11-2079-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/fc80bef82e48/Beilstein_J_Org_Chem-11-2079-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/ec4e5c5ae657/Beilstein_J_Org_Chem-11-2079-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/638cfeab5d4b/Beilstein_J_Org_Chem-11-2079-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/879c6b157d7d/Beilstein_J_Org_Chem-11-2079-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/defd/4660966/c179d0be0b3e/Beilstein_J_Org_Chem-11-2079-g007.jpg

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