Fatp1 Deficiency Affects Retinal Light Response and Dark Adaptation, and Induces Age-Related Alterations

Abstract

FATP1 is involved in lipid transport into cells and in intracellular lipid metabolism. We showed previously that this protein interacts with and inhibits the limiting-step isomerase of the visual cycle RPE65. Here, we aimed to analyze the effect of Fatp1-deficiency in vivo on the visual cycle, structure and function, and on retinal aging. Among the Fatp family members, we observed that only Fatp1 and 4 are expressed in the control retina, in both the neuroretina and the retinal pigment epithelium. In the neuroretina, Fatp1 is mostly expressed in photoreceptors. In young adult Fatp1−/− mice, Fatp4 expression was unchanged in retinal pigment epithelium and reduced two-fold in the neuroretina as compared to Fatp1+/+ mice. The Fatp1−/− mice had a preserved retinal structure but a decreased electroretinogram response to light. These mice also displayed a delayed recovery of the b-wave amplitude after bleaching, however, visual cycle speed was unchanged, and both retinal pigment epithelium and photoreceptors presented the same fatty acid pattern compared to controls. In 2 year-old Fatp1−/− mice, transmission electron microscopy studies showed specific abnormalities in the retinas comprising choroid vascularization anomalies and thickening of the Bruch membrane with material deposits, and sometimes local disorganization of the photoreceptor outer segments. These anomalies lead us to speculate that the absence of FATP1 accelerates the aging process.

Acyl-CoA Metabolism and Partitioning

“…In the retina, FATP1 physically interacts with lecithin retinol-acyltransferase (LRAT) and retinal pigment epithelium isomerase (RPE65) to inhibit isomerase activity (17). LRAT uses an acyl-CoA (frequently 16:0) to esterify all- trans retinal to all- trans retinal ester.…”

“…LRAT uses an acyl-CoA (frequently 16:0) to esterify all- trans retinal to all- trans retinal ester. This substrate for RPE65 converts the retinal ester back to 11- cis retinal in a process that reforms rhodopsin in the visual cycle (17). An analysis of the neuroretina and retinal pigment epithelium from Fatp1 −/− and control mice shows no differences in FA composition, and it was speculated that FATP1 directs FA into the mitochondria (similar to its effects when overexpressed in myotubes and rat muscle) and that its absence diminishes energy production from FA, thereby accelerating ageing in retinas from aged mice (17).…”

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…Fatty acid transport proteins (FATP)-1, FATP-4 and CD36 are the predominant transporters expressed on blood-brain barrier endothelial cells (Mitchell et al, 2011). Very low-density lipoprotein receptor (VLDLR) (Donati et al, 2006), FATP-1 and 4 (Chekroud et al, 2012) are also expressed in RPE and photoreceptors. Thus, fatty acid transport to the retina is inferred although more evidence is still needed.…”

Fatty acid transport protein 1 regulates retinoid metabolism and photoreceptor development in mouse retina

“…In the mouse, Fatp1 and another member of the FATP family, Fatp4, are both expressed in the neural retina (NR) and RPE; in the NR, Fatp1 is mostly expressed in PRs [14]. Both proteins possess long and very long chain FA acyl-CoA synthetase activity [15,16].…”