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A. Taylor, J. Handa, R. H. Nagaraj, F. Shang, W. Jiao, M. Brownlee, T. Uchiki; Association Between Diet-Induced Advanced Glycation End Products, AMD and Cataract. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4179.
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Epidemiological studies show that consumption of high glycemic index (GI) foods, which raise blood glucose levels rapidly, is related to increased risk for prevalence and progress of cataract and/or age-related macular degeneration (AMD) .
ARPE-19 and lens cells in culture were used to model the accumulation of advanced glycation end products (AGE) when the lysosomal proteolytic pathways (LPP) or ubiquitin proteolytic pathways (UPP) were or were not inhibited. Glucose, fructose or methylglyoxal, a sugar metabolite, were used to treat cells.
In corroboration of our hypothesis that elevated sugar metabolite-induced impairment of protein degradation, is due to- and results in- the accumulation of cytotoxic AGEs in cells and is pathogenic, we demonstrated that AGEs are 2-9 fold higher in old human lenses, and >3 fold higher in retina and lens of mice fed the high GI food. Unlike mild oxidative modification or deamidation which enhance rates of UPP-dependent degradation, AGE-modification of proteins decreases their susceptibility to degradation and decreases the efficacy of the LPP and UPP, but not of the proteasome. Importantly, inhibition of the UPP places a burden on the LPP and vice versa. This indicates a novel interaction between these pathways with respect to degradation of AGE-proteins.
Lens and RPE use LPP and UPP to degrade AGE-proteins. AGE modification of intracellular proteins reduces cellular proteolytic capacity and reduces accessibility of substrates to UPP. These result in enhanced accumulation of pathogenic AGEs upon aging. The interaction between the LPP and UPP is altered upon AGE-stress. These changes are etiologic for AMD and cataract, and probably, CVD, type 2 diabetes and other age-related syndromes.Funding: NIH RO1 EY13250; RO1-EY011717, Johnson and Johnson Focused Giving, AHAF,USDA 1950-510000-060-02S,
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