Dyslipidemia: type 1 diabetes vs. type 2 diabetes

Khiari, M.; Zribi, S.; Zahra, Hager; Mizouri, Ramla; Mahjoub, Faten; Berriche, O.; Jamoussi, H.

doi:10.1530/endoabs.56.p424

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“…Increase in ROS damages the mitochondria, and ultimately resulting in the development of diabetic retinopathy. Diabetic patients generally present abnormalities in their lipid metabolism, and type 2 diabetic patients have higher triglyceride levels compared to type I diabetic patients 26,27 ; similar phenomenon is also observed in animal models 7,10 . We have shown that the activation of Rac1-Nox2-ROS signaling is accelerated and exacerbated in the retinal vasculature in type 2 diabetic experimental models compared to type 1 diabetic models.…”

Section: Discussionmentioning

confidence: 52%

Regulation of serine palmitoyl-transferase and Rac1–Nox2 signaling in diabetic retinopathy

Alka

Mohammad

Kowluru

2022

Sci Rep

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Hyperlipidemia is considered as one of the major systemic factors associated with the development of diabetic retinopathy, and animal models have documented that its presence in a hyperglycemic environment exacerbates cytosolic ROS production (via activation of the Rac1–Nox2 axis) and mitochondrial damage. Hyperglycemia also accelerates Rac1 transcription via dynamic DNA methylation–hydroxymethylation of its promoter. In diabetes, ceramide metabolism in the retina is impaired and its accumulation is increased. Our aim was to investigate the effect of inhibition of the rate limiting enzyme of the de novo ceramide biosynthesis, serine palmitoyl-transferase (SPT), on Rac1 activation in diabetic retinopathy. Using human retinal endothelial cells, transfected with SPT-siRNA, and incubated in 20 mM d-glucose in the presence or absence of 50 µM palmitate (glucolipotoxic and glucotoxic, respectively), activities of Rac1 and Nox2, and ROS levels were quantified. For Rac1 transcriptional activation, 5 hydroxymethyl cytosine (5hmC) levels at its promoter were quantified. Key parameters were confirmed in retinal microvessels from streptozotocin-induced diabetic mice on a normal diet (type 1 diabetic model) or on a high-fat diet (45% kcal, type 2 diabetic model), injected intravitreally with SPT-siRNA. Compared to normal glucose, cells in high glucose, with or without palmitic acid, had increased Rac1–Nox2–ROS signaling, Rac1 transcripts and 5hmC levels at its promoter. Inhibition of SPT by SPT-siRNA or myriocin prevented glucotoxic- and glucolipotoxic-induced increase in Rac1–Nox2–ROS signaling and 5hmC at the Rac1 promoter. Similarly, in both type 1 and type 2 diabetic mouse models, SPT-siRNA attenuated the increase in the Rac1–Nox2–ROS axis and 5hmC at the Rac1 promoter. Thus, inhibition of the rate limiting enzyme of ceramide de novo biosynthesis, SPT, regulates activation of DNA methylation–hydroxymethylation machinery and prevents increased Rac1 transcription. This ameliorates the activation of Rac1–Nox2 signaling and protects the mitochondria from damaging cytosolic ROS, which prevents accelerated capillary cell loss. These results further raise the importance of regulating lipid levels in diabetic patients with dyslipidemia.

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