Photoreceptor Death, Thanks to a Low-Fat Diet

Photoreceptors have a phenomenally high metabolic rate – they’re the reason that the retina uses more oxygen per unit mass than any other tissue in the body. The current dogma is that the mitochondria-packed photoreceptors consume copious amounts of glucose to satisfy their metabolic demand… and the failure to supply those demands leads to neovascularization of the macula.

That dogma is being challenged, though – and it started with just a few observations. Children with De Vivo disease have an autosomal dominant developmental disorder. It’s caused by a deficiency of the GLUT1 glucose transporter that is responsible for the low level of basal glucose uptake that is required to sustain respiration in all cells. These children experience developmental delays, microcephaly, and many seizures and other neurological phenomena. It goes to show the importance of glucose for brain function – but there’s one odd finding: their vision is completely normal. Might there be alternative energy substrates for the retina?

That was the question that Joyal et al. (1) asked, noting that lipid β-oxidation occurs in other tissues with high metabolic demand – like the heart and skeletal muscle – and the enzymes responsible for this are also expressed in the eye (2). Transgenic mice were the obvious starting point for their investigation, so they examined Vldlr-/- mutants. The very-low-density lipoprotein receptor (Vldlr) is expressed in many tissues with a high metabolic rate, and facilitates the uptake of triglyceride-derived fatty acid into cells, whereupon lipid β-oxidation occurs, feeding Krebs cycle, and generating energy. The vldlr protein also happens to be present in photoreceptors; VLDLR deletion in humans causes maculopathy, and Vldlr-/- mice develop RAP-like retinal vascular lesions.

Using these mice, they found a link between energy metabolism and neovascular disease – a combination of elegant photoreceptor-specific gene silencing techniques, 3D scanning electron microscopy of photoreceptor mitochondria and some gene microarray experiments established that photoreceptors perform lipid β-oxidation, and require Vldr to do so – and that this was under the control of a “free fatty acid sensor”, Ffar1, that curbs glucose uptake when fatty acid levels are high, by suppressing Glut1 expression. To quote the study’s senior investigator, Louis Smith of Boston Children’s Hospital, “When blood lipids are elevated, the lipid sensor [Ffar1] says, ‘we don’t need glucose, we have enough lipids here,’ and it shuts off glucose uptake.” 

In Vldlr-/- mice, Ffar1 activation leads to “starving” photoreceptors. When the researchers characterized what happened next, they found that this led to a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG), which promotes the stabilization of hypoxia-induced factor 1α (Hif1α)… which led to the photoreceptors of these Vldlr-/- mice to secrete our old friend VEGF-A, and with it, macular neovascularization. The authors concluded, “Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases” (1).

This clearly has therapeutic potential. It’s becoming increasingly clear that rising metabolic dysfunction is a function of the aging retina, and a characteristic of many disease states. What this work suggests is that, if lipid sensors work in human photoreceptors as they do in mice, then Ffar1 could be a new therapeutic target that is, crucially, upstream of VEGF. Helpfully, Ffar inhibitor drugs exist today, and are currently under clinical trial evaluation for the treatment of diabetes. Watch this space.