Metabolomics reveals soluble epoxide hydrolase as a therapeutic target for high- sucrose diet- mediated gut barrier dysfunction

• 成果类型: Article
• 署名作者: Lin, Ai-Zhi; Fu, Xian; Jiang, Qing; Zhou, Xue; Hwang, Sung Hee; Yin, Hou-Hua; Ni, Kai-Di; Pan, Qing-Jin; He, Xin; Zhang, Ling-Tong; Meng, Yi-Wen; Liu, Ya-Nan; Hammock, Bruce D.; Liu, Jun-Yan
• 署名单位: Chongqing Medical University; Chongqing Medical University; University of California System; University of California Davis; University of California System; University of California Davis
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12759
• DOI: 10.1073/pnas.2409841121
• 发表日期: 2024-11-26
• 关键词: insulin-resistance; obesity; inhibitor; HEALTH

摘要

Highsucrose diet (HSD) was reported as a causative factor for multiorgan injuries. The underlying mechanisms and therapeutic strategies remain largely uncharted. In the present study, by using a metabolomics approach, we identified the soluble epoxide hydrolase (sEH) as a therapeutic target for HSD- mediated gut barrier dysfunction. Specifically, 16- week feeding on an HSD caused gut barrier dysfunction, such as colon inflammation and tight junction impairment in a murine model. A metabolomics analysis of mouse colon tissue showed a decrease in the 5(6)- epoxyeicosatrienoic acid [5(6)-EET] level and an increase in soluble epoxide hydrolase, which is related to HSD- mediated injuries to the gut barrier. The mice treated with a chemical inhibitor of sEH and the mice with genetic intervention by intestinal- specific knockout of the sEH gene significantly attenuated HSD- caused intestinal injuries by reducing HSD- mediated colon inflammation and improving the impaired tight junction caused by an HSD. Further, in vitro studies showed that treatment with 5(6)-EET, but not its hydrolytic product 5,6- dihydroxyeicosatrienoic acid (5,6- DiHET), significantly ablated high sucrose- caused intestinal epithelial inflammation and impaired tight junction. Additionally, 5(6)-EET is anti- inflammatory and improves gut epithelial tight junction while 5,6-DiHET cannot do so. This study presents an underlying mechanism of and a therapeutic strategy for the gut barrier dysfunction caused by an HSD.