Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis—either because of diabetes or because of FAS gain of function—was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear.

Prevalence and risk factors of diabetic retinopathy among Chinese adults with type 2 diabetes in a suburb of Shanghai, China

“…Moreover, clinical studies have proved that hyperglycaemia and dyslipidemia can impair the retina synergistically or additively. For example, glucose-mediated de novo lipogenesis in photoreceptors can drive early DR [ 53 ].…”

Diabetic retinopathy: Involved cells, biomarkers, and treatments

“…Another important diabetes-associated variation in photoreceptor cells is de novo retinol lipogenesis. The main reason for this shift is the activation of fatty acid synthase by hyperglycemia ( Rajagopal et al, 2021 ). This shift coupled with other changes in photoreceptors may make up the early pathological mechanism of angiogenesis in early DR ( Rajagopal et al, 2021 ).…”

“…The main reason for this shift is the activation of fatty acid synthase by hyperglycemia ( Rajagopal et al, 2021 ). This shift coupled with other changes in photoreceptors may make up the early pathological mechanism of angiogenesis in early DR ( Rajagopal et al, 2021 ). Neurovascular coupling may directly be impacted by diabetes-induced lipid perturbations at photoreceptor synapses ( Nippert et al, 2018 ).…”

Evaluating the clinical utility of measuring levels of factor H and the related proteins

“…So far, FHRs haven't been reported for vitreous, aqueous humor, or tears, but this could be of major interest. Lastly, the role of the complement system has been implicated in various other ocular diseases namely autoimmune uveitis, glaucoma, and diabetes retinopathy and myopia, but the involvement of the FH protein family has thus far not been investigated (Bansal and Gupta, 2020;Clark and Bishop, 2018;Fiedorowicz et al, 2021;García-Gen et al, 2021;Gui et al, 2020;Jha et al, 2007;Rajagopal et al, 2021;Sundstrom et al, 2018;Torok et al, 2013;Youngblood et al, 2019;Zhang et al, 2020).…”