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Published on: April 7, 2023
High glucose impairs cognitive function by inducing lipid droplet accumulation through lactylation of HSD17B10 at
Jingxi Xu1, Jingxue Cao1, Xing Yang2
1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P.R. China.
Abstract:
High glucose is known to impair cognitive function in individuals with type 2 diabetes, though the precise mechanisms remain unclear. In this study, guided by lactylome analysis, we demonstrate that high glucose induces HSD17B10 K105 lactylation in hippocampal neurons by upregulating lactyltransferase Aars1, which reduces HSD17B10 enzyme activity, subsequently resulting in impaired breakdown and excessive accumulation of lipid droplets, and ultimately leading to neuronal apoptosis and cognitive decline. Notably, a short peptide that competitively inhibits HSD17B10 K105 lactylation remarkably mitigates cognitive impairment in diabetic mice. Furthermore, results from a large-scale prospective cohort study reveal that elevated plasma HSD17B10 K105 lactylation serves as an independent predictor of cognitive dysfunction in patients with type 2 diabetes. These findings uncover a critical pathway linking high glucose-induced lactylation to lipid accumulation and neuronal cell death, highlighting promising molecular targets for the prevention and treatment of diabetes-associated cognitive impairment.
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