Zou Rong, Cai Jinrui, Chen Tianyu, Mo Wenhui, Qian Hao, Zhu Xianjun, Zhang Lin
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China.
BMC Biol. 2025 Apr 17;23(1):103. doi: 10.1186/s12915-025-02212-z.
High-fat diet (HFD) was suggested to be associated with several retinal diseases, including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Nevertheless, our understanding of the mechanisms governing retinal lipid metabolic homeostasis remains limited, with little attention focused on the influence of HFD on different retinal cell types. To address this gap, we established a high-fat model using mice fed with HFD for a duration of 6 months. Then, we conducted a comparative analysis of the retinal lipidome and proteome between normal diet (ND) and HFD-fed mice to explore the impacts of HFD on retinal lipid metabolism and gene expression network. Furthermore, we also investigated the impacts of HFD on retina in single-cell resolution by single-cell transcriptome sequencing.
We found that a long-term HFD significantly altered the lipid composition of the retina, with a dramatically elevated cholesterylesters (CE), phosphatidylcholine (PC), and phosphatidylglycerol (PG) level and a decreased eicosanoid level. Proteomic analysis revealed that the primary bile acid biosynthesis pathway was over-activated in HFD retinas. By using single-cell transcriptome analysis, we identified different regulation of gene expression in MG and rod cells in a high-fat environment, whereas the previously identified activation of the bile acid synthesis pathway was predominantly found in MG cells, and may be regulated by alternative pathways of bile acid synthesis, suggesting the critical roles of MG cells in retinal lipid metabolism.
Taken together, by multi-omics studies, we unveiled that HFD leading to the development of retinal diseases may be regulated by alternative pathways of bile acid synthesis, and our study will shed light on the treatment of these diseases.
高脂饮食（HFD）被认为与多种视网膜疾病有关，包括年龄相关性黄斑变性（AMD）、青光眼和糖尿病视网膜病变（DR）。然而，我们对视网膜脂质代谢稳态调控机制的理解仍然有限，很少有人关注高脂饮食对不同视网膜细胞类型的影响。为了填补这一空白，我们建立了一个高脂模型，用高脂饮食喂养小鼠6个月。然后，我们对正常饮食（ND）和高脂饮食喂养的小鼠的视网膜脂质组和蛋白质组进行了比较分析，以探讨高脂饮食对视网膜脂质代谢和基因表达网络的影响。此外，我们还通过单细胞转录组测序在单细胞分辨率下研究了高脂饮食对视网膜的影响。
我们发现长期高脂饮食显著改变了视网膜的脂质组成，胆固醇酯（CE）、磷脂酰胆碱（PC）和磷脂酰甘油（PG）水平显著升高，类花生酸水平降低。蛋白质组学分析表明，初级胆汁酸生物合成途径在高脂饮食的视网膜中过度激活。通过单细胞转录组分析，我们发现在高脂环境下，MG细胞和视杆细胞中基因表达存在不同的调控，而先前确定的胆汁酸合成途径的激活主要在MG细胞中发现，并且可能由胆汁酸合成的替代途径调控，这表明MG细胞在视网膜脂质代谢中起关键作用。
综上所述，通过多组学研究，我们揭示了导致视网膜疾病发展的高脂饮食可能受胆汁酸合成替代途径的调控，我们的研究将为这些疾病的治疗提供线索。
