Cholesterol Homeostasis Regulated by ABCA1 is Critical for Retinal Ganglion Cell Survival

Overview

Journal Sci China Life Sci

Specialties Biology
Science

Date 2022 Jul 13

PMID 35829808

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

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