Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin  

作　　者：Lewei Dong Jian Xiao Shuai Liu Gang Deng Yacheng Liao Beibei Chu Xiaolu Zhao Bao-Liang Song Jie Luo 

机构地区：[1]College of Life Sciences,Taikang Center for Life and Medical Sciences,Hubei Key Laboratory of Cell Homeostasis,Wuhan University,Wuhan 430072,China [2]College of Veterinary Medicine,Henan Agricultural University,Zhengzhou 450046,China

出　　处：《Science China(Life Sciences)》2023年第8期1786-1799,共14页中国科学（生命科学英文版）

基　　金：supported by the China Postdoctoral Science Foundation Grant(2021M692478);the Ministry of Science and Technology of China(2018YFA0800703);the National Natural Science Foundation of China(32293203,31771568);111 Project of Ministry of Education of China(B16036);the support from the Tencent Foundation through the XPLORER PRIZE。

摘　　要：Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.

关 键 词：CHOLESTEROL PEROXISOME LYSOSOME peroxisomal disorders X-ALD CYCLODEXTRIN ABCD1 VLCFA 

分 类 号：R363[医药卫生—病理学]