Cholesterol homeostasis regulated by ABCA1 is critical for retinal ganglion cell survival  

作　　者：Jialiang Yang Yuhong Chen Tongdan Zou Bai Xue Fang Yang Xiangzhou Wang Yibo Huo Boyun Yan Yuxia Xu Shiyu He Yi Yin Jing Wang Xiong Zhu Lin Zhang Yu Zhou Zhengfu Tai Ping Shuai Man Yu Qian Luo Yilian Cheng Bo Gong Xianjun Zhu Jing Zhang Xinghuai Sun Ying Lin Houbin Zhang Zhenglin Yang 

机构地区：[1]Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu 610072,China [2]Department of Ophthalmology and Visual Science,Eye and Ear Nose Throat(ENT)Hospital,Fudan University,Shanghai 200032,China [3]School of Optoelectronic Science and Engineering,University of Electronic Science and Technology of China,Chengdu 611731,China [4]Institute of Chengdu Biology,Sichuan Translational Medicine Hospital,Chinese Academy of Sciences,Chengdu 610093,China [5]Department of Ophthalmology,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu 610072,China [6]Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences,Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital,Chengdu 610072,China

出　　处：《Science China(Life Sciences)》2023年第2期211-225,共15页中国科学（生命科学英文版）

基　　金：supported by the National Precision Medicine Project(2016YFC0905200);the National Natural Science Foundation of China(81790643,82121003,81570882,81770935,81670853,81271005);the grant from Chinese Academy of Medical Sciences(2019-I2M-5-032);the grant from the Department of Science and Technology of Sichuan Province(2021YFS0404,2021FS0369,2020YJ0445,2019JDJQ0031,2022JDTD0024)。

摘　　要：Genome-wide association studies have suggested a link between primary open-angle glaucoma and the function of ABCA1.ABCA1 is a key regulator of cholesterol efflux and the biogenesis of high-density lipoprotein(HDL) particles. Here, we showed that the POAG risk allele near ABCA1 attenuated ABCA1 expression in cultured cells. Consistently, POAG patients exhibited lower ABCA1 expression, reduced HDL, and higher cholesterol in white blood cells. Ablation of Abca1 in mice failed to form HDL, leading to elevated cholesterol levels in the retina. Counting retinal ganglion cells(RGCs) by using an artificial intelligence(AI) program revealed that Abca1-deficient mice progressively lost RGCs with age. Single-cell RNA sequencing(scRNA-seq) revealed aberrant oxidative phosphorylation in the Abca1-/-retina, as well as activation of the mTORC1 signaling pathway and suppression of autophagy. Treatment of Abca1-/-mice using atorvastatin reduced the cholesterol level in the retina,thereby improving metabolism and protecting RGCs from death. Collectively, we show that lower ABCA1 expression and lower HDL are risk factors for POAG. Accumulated cholesterol in the Abca1-/-retina causes profound aberrant metabolism, leading to a POAG-like phenotype that can be prevented by atorvastatin. Our findings establish statin use as a preventive treatment for POAG associated with lower ABCA1 expression.

关 键 词：ABCA1 GLAUCOMA retinal ganglion cell HDL CHOLESTEROL ATORVASTATIN 

分 类 号：R543.5[医药卫生—心血管疾病]