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Lipotoxicity reduces β cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules

Research output: Contribution to journalArticlepeer-review

Yunting Zhou, Wei Li, Junming Zhou, Juan Chen, Xiaohang Wang, Min Cai, Fengfei Li, Wei Xu, Per Ola Carlsson, Zilin Sun

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalExperimental Cell Research
Volume380
Issue number1
DOIs
Published1 Jul 2019

King's Authors

Abstract

Background: Islet stellate cells (ISCs)activation is mainly associated with islet fibrosis, which contributes to the progression of type 2 diabetes. However, the molecular mechanism underlying this process is not fully understood. Methods: In order to investigate this process the current study examined ectopic fat accumulation in rats with high-fat diet (HFD)induced obesity. Levels of lipotoxicity-induced ISC activation and islet function were assessed via intraperitoneal glucose and insulin tolerance tests, and immunohistochemistry. The expression of lipid metabolism- and ISC activation-related markers was evaluated in cultured ISCs treated with palmitic acid (PA)using quantitative PCR and western blotting. We also overexpressed sterol regulatory element-binding protein (SREBP)-1c in ISCs by lentiviral transduction, and assessed the effects on insulin release in co-cultures with isolated rat islets. Results: HFD increased body weight and ectopic fat accumulation in pancreatic islets. Lipotoxicity caused progressive glucose intolerance and insulin resistance, upregulated α-smooth muscle actin, and stimulated the secretion of extracellular matrix. Lipotoxicity reduced the expression of lipid metabolism-related molecules in ISCs treated with PA, especially SREBP-1c. Overexpression of SREBP-1c in ISCs improved islet viability and insulin secretion in co-cultures. Conclucions: These results indicate that lipotoxicity-induced ISC activation alters islet function via regulation of lipid metabolism, suggesting that therapeutic strategies targeting activated ISC may be an effective treatment for prevention of ISC activation-associated islet dysfunction.

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