Tranilast protects pancreatic beta-cells from palmitic acid-induced lipotoxicity via FoxO-1 inhibitionopen access
- Authors
- Choi, Hye-Eun; Kim, Dong Young; Choi, Mi Jin; Kim, Jea Il; Kim, Ok-Hee; Lee, Jinwook; Seo, Eunhui; Cheon, Hyae Gyeong
- Issue Date
- Jan-2023
- Publisher
- NATURE PORTFOLIO
- Citation
- SCIENTIFIC REPORTS, v.13, no.1
- Journal Title
- SCIENTIFIC REPORTS
- Volume
- 13
- Number
- 1
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/87062
- DOI
- 10.1038/s41598-022-25428-3
- ISSN
- 2045-2322
- Abstract
- Tranilast, an anti-allergic drug used in the treatment of bronchial asthma, was identified as an inhibitor of the transcription factor Forkhead box O-1 (FoxO-1) by high throughput chemical library screening in the present study. Based on FoxO-1's role in apoptotic cell death and differentiation, we examined the effect of tranilast on palmitic acid (PA)-induced cell damage in INS-1 cells. Tranilast substantially inhibited lipoapoptosis and restored glucose-stimulated insulin secretion under high PA exposure. Moreover, PA-mediated downregulation of PDX-1, MafA, and insulin expression was attenuated by tranilast. PA-induced oxidative and ER stress were also reduced in the presence of tranilast. These protective effects were accompanied by increased phosphorylation and decreased nuclear translocation of FoxO-1. Conversely, the effects of tranilast were diminished when treated in transfected cells with FoxO-1 phosphorylation mutant (S256A), suggesting that the tranilast-mediated effects are associated with inactivation of FoxO-1. Examination of the in vivo effects of tranilast using wild type and diabetic db/db mice showed improved glucose tolerance along with FoxO-1 inactivation in the pancreas of the tranilast-treated groups. Thus, we report here that tranilast has protective effects against PA-induced lipotoxic stress in INS-1 cells, at least partly, via FoxO-1 inactivation, which results in improved glucose tolerance in vivo.
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