The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE

Abstract

The accumulation of lipids within drusen, the epidemiologic link of a high fat diet, and the identification of polymorphisms in genes involved in lipid metabolism that are associated with disease risk, have prompted interest in the role of lipid abnormalities in AMD. Despite intensive investigation, our understanding of how lipid abnormalities contribute to AMD development remains unclear. Lipid metabolism is tightly regulated, and its dysregulation can trigger excess lipid accumulation within the RPE and Bruch's membrane. The high oxidative stress environment of the macula can promote lipid oxidation, impairing their original function as well as producing oxidation-specific epitopes (OSE), which unless neutralized, can induce unwanted inflammation that additionally contributes to AMD progression. Considering the multiple layers of lipid metabolism and inflammation, and the ability to simultaneously target multiple pathways, microRNA (miRNAs) have emerged as important regulators of many age-related diseases including atherosclerosis and Alzheimer's disease. These diseases have similar etiologic characteristics such as lipid-rich deposits, oxidative stress, and inflammation with AMD, which suggests that miRNAs might influence lipid metabolism in AMD. In this review, we discuss the contribution of lipids to AMD pathobiology and introduce how miRNAs might affect lipid metabolism during lesion development. Establishing how miRNAs contribute to lipid accumulation in AMD will help to define the role of lipids in AMD, and open new treatment avenues for this enigmatic disease.

Keywords: Age-related macular degeneration; Inflammation; Lipids; Oxidative stress; Retinal pigmented epithelium; microRNA.

Figure 1.

Lipid-related pathogenic mechanisms in AMD. Lipids accumulate in the sub-RPE and sub-retinal space. Various oxidative sources including aging, cigarette smoking, cellular metabolism, and sunlight cause the oxidation of lipid molecules, which induces inflammation in part, through complement and inflammasome activation, and cytokine production in the RPE and/or microglia/macrophages. In addition, a high fat diet and the phagocytosis of photoreceptor outer segments (POS) by the RPE are major sources of lipid accumulation. Monocytes/macrophages/microglia are recruited and further differentiated by various cytokines, to induce inflammation and modify lipid transport metabolism. These processes worsen lipid oxidation and promote the accumulation of inflammatory molecules during drusenogenesis. The combination of direct injury from oxidized lipids and dysregulated, chronic inflammation can contribute to RPE degeneration that can mediate to photoreceptor death (outer retinal atrophy) resulting vision loss and AMD.

Figure 2.

Scheme of lipid metabolism and miRNAs with the potential to regulate lipid pathways within the RPE during AMD progression. The RPE cell in the cholesterol poor rod (green) dominated perifoveal macula on the left is ingesting systemically delivered lipoproteins via receptors like LDLR and SR-BI for LDL and HDL uptake, or oxidized LDLs through CD36 on its basolateral side. In addition, the apical RPE is removing cholesterol for photoreceptors by reverse cholesterol transport. The miRNAs that can regulate these processes are listed. Dysregulation of this process can result in subretinal drusenoid deposit (SDD) formation.