Abstract
Purpose :
Dietary glycemic index (GI) indicates how fast glucose from dietary carbohydrates enters the bloodstream after consuming a food item. Dietary GI has been found as a risk factor for developing blinding diseases, such as age-related macular degeneration and cataracts. The retinas of mice fed a high GI diet for 12 months show photoreceptor loss, which is accelerated in Nrf2 knockout mice. To assess the molecular consequences of GI in WT and Nrf2-/- mice, we have evaluated transcriptomic changes in the retinas and livers after exposure to a high (HGI) or low glycemic (LGI) diet.
Methods :
C57BL/6 (WT) and Nrf2-/- mice were aged from 6 to 18 months while feeding on an LGI diet of 70% amylose + 30% amylopectin or an HGI diet of 100% amylopectin. RNA from retinas and livers was used for RNA-seq. Bioinformatic analyses involved the Bioconductor pipeline of edgeR and limma. Differential analysis was set at two fold change and p-value of 0.05, before pathway annotation with gProfiler.
Results :
Principal component analysis showed distinct genotype-based clustering among WT and Nrf2-/- livers. WT HGI mice displayed higher expression of glutathione pathway genes, such as glutathione S-transferase, relative to LGI. Notably, glutathione genes were reduced by 2-6 fold in Nrf2-/- livers, regardless of GI, indicating gene-diet interactions. The expression of retinol metabolism genes, including aldehyde dehydrogenase and UDP glucuronosyltransferase, were also reduced in Nrf2-/- livers. Mitochondrial OXPHOS genes, involved in complexes 1 and 5, as well as late endosomal/lysosomal autophagy genes, were upregulated in WT HGI livers but did not show any response to GI in Nrf2-/- livers. Retinal transcriptome analysis is in progress.
Conclusions :
The interaction between genetics and dietary GI in WT and Nrf2-/- mice can help explain the differences in phenotype and disease susceptibility. We reason that Nrf2-/- animals experience reduced ability to respond to glycemia-induced stress due to attenuated antioxidant response systems. This leads to a lowered ability to sanitize the cell of damaging molecules. Retinal transcriptomic analysis would reveal a pathmechanistic relationship between GI, genotype, and retinal degeneration.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.