488-P: Phosphatidate Phosphatase Lipin1 Is Involved in the Development of Diabetic Encephalopathy by Regulating the Homeostasis of Mitochondria-Associated Endoplasmic Reticulum (MAMs)

• Published in: Diabetes (New York, N.Y.) Vol. 73; p. 1
• Main Authors: Chen, Shihong, Zhuang, Xianghua, Yu, Shuyan, Huang, Shan, Han, Xiaolin
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01-06-2024
• Subjects: Animal models; Cell culture; Central nervous system; Cognitive ability; Diabetes; Diabetes mellitus; Encephalopathy; Endoplasmic reticulum; Hippocampus; Homeostasis; Hyperglycemia; Mitochondria; Mitophagy; Neurons; Pathogenesis; Phosphatidate phosphatase; Phospholipids; Structure-function relationships
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db24-488-P

Introduction & Objective: Diabetic encephalopathy (DE) is a common chronic central nervous system complication without clear elucidation of pathogenesis as well as effective therapy currently. Mitochondria-associated endoplasmic reticulum membrane is a dynamic contact site connecting mitochondrial membrane with endoplasmic reticulum (ER) membrane, where phospholipid components are exchanged to each other. Our previous work has revealed that Lipin1, a critical enzyme related to phospholipid synthesis, involves in the pathogenesis of DE. However, it needs further investigation whether Lipin1 affects cognitive function via regulating the homeostasis of MAMs in neurons of DE. Methods: We used C57BL/6J mice in vivo and HT-22 neuronal cells in vitro to construct DE models and Lipin1-targeted regulation models to detect any changes in MAMs, ER stress, mitophagy, dendritic structure and cognitive function. Statistics were analyzed by using t-test and one-way ANOVA. Results: Here, we demonstrate that Lipin1 is significantly reduced in hippocampus of DE mice. Knockdown of Lipin1 within hippocampus or neurons induces significant structural and functional impairment of MAMs with the enhancement of ER stress and mitophagy, and then leads to impaired dendritic structure and cognitive dysfunction, similar to that observed in DE. In contrast, up-regulation of Lipin1 within hippocampus or neurons in the DE model ameliorates this cascade of dysfunction. Conclusion: Lipin1 deficiency in response to chronic hyperglycemia contributes to the imbalance of MAMs homeostasis in hippocampal neurons, accompanying the enhancement of ER stress and mitophagy, and finally leads to cognitive deficits observed in DE.