Usoltseva Anna S, Litwin Christopher, Lee Michael, Hill Colton, Cai Jiyang, Chen Yan
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
FASEB J. 2024 Dec 13;38(24):e70249. doi: 10.1096/fj.202400981R.
Dysregulated lipid metabolism, characterized by the accumulation of lipid deposits on Bruch's membrane and in drusen, is considered a key pathogenic event in age-related macular degeneration (AMD). The imbalance of lipid production, usage, and transport in local tissues, particularly in the retinal pigment epithelium (RPE), is increasingly recognized as crucial in AMD development. However, the molecular mechanisms governing lipid metabolism in the RPE remain elusive. LIPIN1, a multifunctional protein acting as both a modulator of transcription factors and a phosphatidate phosphatase (PAP1), is known to play important regulatory roles in lipid metabolism and related biological functions, such as inflammatory responses. While deficits in LIPIN1 have been linked to multiple diseases, its specific roles in the retina and RPE remain unclear. In this study, we investigated LIPIN1 in RPE integrity and function using a tissue-specific knockout animal model. The clinical and histological examinations revealed age-dependent degeneration in the RPE and the retina, along with impaired lipid metabolism. Bulk RNA sequencing indicated a disturbance in lipid metabolic pathways. Moreover, these animals exhibited inflammatory markers reminiscent of human AMD features, including deposition of IgG and C3d on Bruch's membrane. Collectively, our findings indicate that LIPIN1 is a critical component of the complex regulatory network of lipid homeostasis in the RPE. Disruption of LIPIN1-mediated regulation impaired lipid balance and contributed to AMD-related pathogenic changes.
脂质代谢失调，其特征为布鲁赫膜和玻璃膜疣上脂质沉积的积累，被认为是年龄相关性黄斑变性（AMD）的关键致病事件。局部组织，特别是视网膜色素上皮（RPE）中脂质生成、利用和运输的失衡，在AMD发展过程中越来越被认为至关重要。然而，RPE中调控脂质代谢的分子机制仍不清楚。LIPIN1是一种多功能蛋白，既是转录因子的调节剂，又是磷脂酸磷酸酶（PAP1），已知在脂质代谢及相关生物学功能（如炎症反应）中发挥重要的调节作用。虽然LIPIN1的缺陷与多种疾病有关，但其在视网膜和RPE中的具体作用仍不清楚。在本研究中，我们使用组织特异性敲除动物模型研究了LIPIN1在RPE完整性和功能中的作用。临床和组织学检查显示RPE和视网膜出现年龄依赖性退化，同时脂质代谢受损。批量RNA测序表明脂质代谢途径受到干扰。此外，这些动物表现出类似于人类AMD特征的炎症标志物，包括IgG和C3d在布鲁赫膜上的沉积。总体而言，我们的研究结果表明LIPIN1是RPE脂质稳态复杂调控网络的关键组成部分。LIPIN1介导的调节破坏会损害脂质平衡，并导致与AMD相关的致病变化。
