期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2113074119
关键词
FIT2; lipid droplets; pancreatic beta cells; ER stress; diet-induced diabetes
资金
- Singapore Ministry of Education grants under its Singapore Ministry of Education Academic Research Fund Tier 2 [MOE2015-T2-2-087, MOE2018-T2-1-085, 2017-T1-001-220, 2019-T1-001-059]
- Nanyang Technological University Singapore
- LKCMedicine Healthcare Research Fund
- Nanyang President's Graduate Scholarship award
- Nanyang Technological University, Singapore
- Singapore National Research Foundation Fellowship award [NRF-NRFF2016-03]
- National University of Singapore via the Life Sciences Institute
- National Research Foundation (NRF) [NRFI2015-05]
- Agency for Science, Technology and Research (A*STAR) Industry Alignment Fund-Industry Collaborative Project [I1901E0040]
- 1.3.5 Project for Disciplines of Excellence grant, West China Hospital, Sichuan University [ZYGD18017]
- Swedish Research Council
- Family Erling-Persson Foundation
- Novo Nordisk Foundation
- Stichting af Jochnick Foundation
- Swedish Diabetes Association
- Scandia Insurance Company Ltd.
- Diabetes Research and Wellness Foundation, Berth von Kantzow's Foundation
- Strategic Research Program in Diabetes at Karolinska Institutet [ERC-2018-AdG 834860 EYELETS]
- Center of Excellence-International Collaboration Initiative Grant [139180012]
- National Natural Science Foundation of China [82070846]
- Wellcome Trust Investigator (WT212625/Z/18/Z) Award
- Medical Research Council Programme grant [MR/R022259/1]
- European Union Horizon2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking [115881]
Western-type diets, high in saturated fatty acids (SFAs), are associated with obesity and diabetes. This study reveals that SFAs, but not unsaturated fatty acids (USFAs), reduce lipid droplets (LDs) in pancreatic beta cells. SFAs induce the degradation of fat storage-inducing transmembrane protein 2 (FIT2), inhibiting LD formation. Reduction of FIT2 in beta cells impairs cellular functions and exacerbates diet-induced diabetes.
Western-type diets are linked to obesity and diabetes partly because of their high-saturated fatty acid (SFA) content. We found that SFAs, but not unsaturated fatty acids (USFAs), reduced lipid droplets (LDs) within pancreatic beta cells. Mechanistically, SFAs, but not USFAs, reduced LD formation by inducing S-acylation and proteasomal, mediated degradation of fat storage-inducing transmembrane protein 2 (FIT2), an endoplasmic reticulum (ER) resident protein important for LD formation. Targeted ablation of FIT2 reduced beta cell LD numbers, lowered beta cell ATP levels, reduced Ca2+ signaling, dampened vesicle exocytosis, down-regulated beta cell transcription factors, up-regulated unfolded protein response genes, and finally, exacerbated diet-induced diabetes in mice. Subsequent mass spectrometry studies revealed increased C16:0 ceramide accumulation in islets of diet-induced diabetes mice lacking beta cell FIT2 Inhibition of ceramide synthases ameliorated the enhanced ER stress and improved insulin secretion. FIT2 was reduced in mouse diabetic islets, and separately, overexpression of FIT2 increased the number of intracellular LDs and rescued SFA-induced ER stress and apoptosis, thereby highlighting the protective role of FIT2 and LDs against beta cell lipotoxicity.
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