Exploring the Role of Hepatic Lipase and Lipid Metabolism in AMD

The goal of my project is to understand how hepatic lipase and dysregulated lipid metabolism are involved in the pathogenesis of AMD. Hepatic lipase (HL) breaks down HDL to smaller particles, and reduced HL may impair the ability of RPE cells to export cholesterol, leading to increased accumulation of large CE- and apoE-HDL rich particles that could cause drusen formation in AMD. For the first aim, we will study the effects of HL knockout and overexpression on cholesterol efflux using polarized 2D iPSC-RPE cultures. For the second aim, we will characterize the retinal phenotype in an HL/EL dKO mouse model and investigate the development of AMD-like retinal degenerative changes with and without a high-fat diet.

Age-related macular degeneration (AMD) is one of the leading causes of severe vision loss in the elderly population. Degenerative changes and physiological changes in the aging retinal pigment epithelium (RPE) layer, which is a major supporting structure to the neuroretina, is a key factor in AMD pathogenesis. Pathways linked to lipid and cholesterol metabolism have been strongly implicated in several AMD genetic studies. Published studies have also shown that cholesterol is secreted from the basal side of the RPE into the choroidal circulation, thereby maintaining cholesterol homeostasis in the retina. Disruptions in clearing cholesterol and triglycerides may result in the accumulation of these lipids in the RPE which impairs cellular function and promotes degenerative changes in the RPE and retina. One of the lipid genes implicated in AMD is LIPC, which encodes for hepatic lipase (HL) that breaks down high-density lipoproteins (HDL) to smaller denser particles to be cleared away by systemic circulation. Reduced expression of LIPC due to mutations in this gene may impair the ability of RPE cells to export cholesterol into the choroidal circulation leading to increased accumulation of large CE- and apoE-HDL rich particles. Using cellular (iPSC derived RPE cultures) and animal models, our study aims to unravel the role of HL in regulating cholesterol efflux and would help in designing targeted therapies for slowing down the disease progression.

To the best of our knowledge, HDL has not been investigated as a major source of druse lipid, nor has it been suggested in the literature that HDL may contribute to druse deposition in AMD in a substantial manner. Our study will establish if HDL accumulation results in RPE pathology and if modulating HDL will result in efflux and clearance of accumulated cholesterol. Well-characterized HL/EL dKO mice can be used as a novel model for studying AMD lipid biogenesis.

Our study will reveal if modulation of LIPC can alter the mechanisms of cholesterol metabolism in RPE both in vitro and in vivo and if they can be associated with AMD by affecting cholesterol efflux pathways. Our study is not only innovative, but it will also extend the existing knowledge about the accumulation of lipid deposits as drusen deposits which are the primary hallmarks of AMD. They will provide insight into the role, mechanisms, and pathways regulating the cholesterol biogenesis in the aging retina and ways to intervene in this step for positive therapeutic application.