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

Abstract

In retinal pigment epithelium (RPE), RPE65 catalyzes the isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol in the visual cycle and controls the rhodopsin regeneration rate. However, the mechanisms by which these processes are regulated are still unclear. Fatty Acid Transport Protein 1 (FATP1) is involved in fatty acid uptake and lipid metabolism in a variety of cell types. FATP1 co-localizes with RPE65 in RPE and inhibits its isomerase activity in vitro. Here, we further investigated the role of FATP1 in the visual cycle using transgenic mice that overexpress human FATP1 specifically in the RPE (hFATP1TG mice). The mice displayed no delay in the kinetics of regeneration of the visual chromophore 11-cis-retinal after photobleaching and had no defects in light sensitivity. However, the total retinoid content was higher in the hFATP1TG mice than in wild type mice, and the transgenic mice also displayed an age-related accumulation (up to 40%) of all-trans-retinal and retinyl esters that was not observed in control mice. Consistent with these results, hFATP1TG mice were more susceptible to light-induced photoreceptor degeneration. hFATP1 overexpression also induced an ~3.5-fold increase in retinosome autofluorescence, as measured by two-photon microscopy. Interestingly, hFATP1TG retina contained ~25% more photoreceptor cells and ~35% longer outer segments than wild type mice, revealing a non-cell-autonomous effect of hFATP1 expressed in the RPE. These data are the first to show that FATP1-mediated fatty acid uptake in the RPE controls both retinoid metabolism in the outer retina and photoreceptor development.

Expression of fatty acid transport protein in retinal pigment cells promotes lipid droplet expansion and photoreceptor homeostasis

“…Similarly, pan-retinal or dRPC-specific expression of dFatp caused a loss of dRPCs of about 10%, resulting in perturbation of the organization of ommatidia in Drosophila retina (Fig 6E and 6F). In contrast to the dRPCs, photoreceptor cell survival (visualized by expression of Rh1-GFP) was unaffected by dFatp overexpression in dRPCs (Fig 6G, left panels, and 6H), which is in agreement with our previous findings in the mouse [30]. Therefore, Fatp -mediated LD accumulation in RPCs does not appear to be deleterious to photoreceptor cells under normal physiological conditions.…”

“…We found that LD accumulation in RPCs induced by ectopic expression of FATP is not toxic to photoreceptors in either Drosophila (this study) or mice [30], suggesting that LDs are not deleterious under normal physiological conditions. In addition to acting as an energy source, LDs may also reduce the cellular sensitivity to ROS.…”

“…This result supports the conservation of hFATP1 and dFatp function in retinal homeostasis. To investigate the role of hFATP1 in lipid storage in the mammalian retina, we employed our previously described transgenic mice [28], in which hFATP1 is overexpressed using the mammalian mRPC-specific VDM2 promoter (referred to as hFATP1TG mice) [30]. LDs in the retinas of WT (C57BL/6, Fig 4A) and hFATP1TG (Fig 4B) mice were detected by staining of neutral lipids with Nile Red.…”

“…Finally, hFatp1 has been shown to directly interact with visual cycle enzymes [38.] Expression of human Fatp1 in mouse RPCs leads to accumulation of retinoids, which are nontoxic to photoreceptors except under conditions of excessive light exposure [30]. Whether or not loss or overexpression of dFatp leads to dysregulation of the visual cycle in flies remains to be established.…”

“…Transgenic mice overexpressing human Fatp1 (hFATP1TG) specifically in the RPCs (driven by the RPC-specific VDM2 promoter) were generated on a C57BL/6J genetic background as previously described [30]. The hFATP1TG mice were maintained on a standard 12 h light (90 lux)/12 h dark cycle at ∼22°C and were fed ad libitum with a standard rodent diet.…”