Abstract
Purpose :
Significant evidence supports the benefits of consuming omega-3 fats, i.e., phospholipids containing DHA (Docosahexaenoic Acid), for human health. DHA is highly concentrated in the brain and retina despite the fact that it cannot be synthesized in these tissues and has to be transported across the blood-brain and blood-retina barrier (BRB). Mechanisms responsible for DHA transport and its retention behind BRB are poorly defined. Previous studies showed that disruption of lysophosphatidylcholine transport leads to DHA depletion, which was accompanied by upregulation of transcriptional factors, the Sterol Regulatory Element-binding Proteins (SREBPs), and might hint at their potential role in the regulation DHA levels. Here, we used mouse genetics to probe the contribution of basal activity of SREBPs in setting the fatty acid composition of phospholipids in the retina.
Methods :
To impair SREBPs’ activity, we knocked out SREBP cleavage-activating protein (SCAP) specifically in the retina. The phospholipid and fatty acid analysis was performed using mass spectrometry. The retinal health, function, and structure were assessed with Optical Coherence Tomography (OCT), fluorescein angiography, electroretinography (ERG), and immunostaining. RNAseq was used to study transcriptional changes.
Results :
Lipidomics analysis of retina-specific SCAP knockout mice showed reduced levels of docosahexaenoic (DHA), arachidonic (AA), and monounsaturated (MUFA) fatty acids, resulting in a simpler fatty acid profile with higher content of saturated fatty acids. Removal of SCAP also led to progressive thinning of the retina and vasculature defects reminiscent of Retinal Angiomatous Proliferation (RAP). Changes in fatty acid composition were different from mice which lack a receptor protein Mfsd2a transporting lysophosphatidylcholine.
Conclusions :
We found that the basal activity of SREBPs in the retina contributes to the fatty acid composition of retinal membranes. The lipid profile of membranes is critical for retinal health and maintenance of the vasculature network. The findings support the rationale to study the role of SREBP transcriptional factors in lipid metabolism in the retina.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.