NIH Reporter #1R01EY037489-01A1

The role of retinal microsomal triglyceride transfer protein in vision

This NIH-funded project investigates the role of retinal microsomal triglyceride transfer protein (MTP) in maintaining lipid balance in the retina, which is crucial for preventing retinal degeneration and preserving vision. The research uses in vivo models to study how MTP regulates lipid transport and homeostasis in retinal pigment epithelium cells, with implications for treating age-related retinal diseases.

Description

Human aging and age-related retinal disease is characterized by dysregulation of lipid processing resulting in the accumulation of pathogenic lipid-rich debris. We propose that assembly of retina-specific lipoproteins balances lipid accumulation inside the cell and allows for the clearance of toxic lipids en masse, thus preserving visual function. Central to retinal lipid homeostasis is the regulation of input and export pathways which define the intracellular pool of RPE lipids and which, when dysregulated, is associated with pathologic lipid accumulation, a hallmark of many degenerative retinal diseases. The RPE manages transport of lipids into and out of the neural retina (NR) and, uptake of fat-soluble vitamins from the choroid as well as the metabolism of ingested outer segment (OS) lipids, lipid recycling to NR, and de novo lipid synthesis. Much of the lipid pool in RPE is stored in lipid droplets (LD); while likely initially protective, excess accumulation of LD can induce cellular dysfunction and toxicity. Lipid packaging and transport occurs via apoprotein B (APOB) containing lipoproteins (Blps); these specialized lipid transport particles made up of structural apo-proteins hold together a lipid core rich in triglycerides and esterified cholesterol. Through the assembly and secretion of Blps, lipids can be removed en masse, thus preventing lipotoxicity. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is the master regulator of Blp assembly. Our studies are the first to develop a metabolically intact, in vivo system demonstrating that local, RPE-specific, MTP activity and Blp assembly and secretion maintain RPE and NR lipid homeostasis. Loss of MTP in the RPE (ΔMttp mouse) decreases RPE-associated Blp, enhances lipid droplet accumulation, retinal cholesterol, and sub-retinal deposits, culminating in retinal degeneration and loss of rod cell function. Patients with age-related retinal degeneration and abetalipoproteinemia (ABL) exhibit progressive vision loss with age despite supplementation with fat-soluble vitamins. We hypothesize that the retina relies on local, RPE-MTP-dependent lipid processing to maintain lipid balance through regulated lipid transport via Blps and lipid droplet upkeep to sustain metabolic synergy with the NR for retinal health.

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