Destabilization of beta Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes

Xiaofeng Zheng, Qing Wei Calvin Ho, Minni Chua, Olga Stelmashenko, Xin Yi Yeo, Sneha Muralidharan, Federico Torta, Elaine Guo Yan Chew, Michelle Mulan Lian, Jia Nee Foo, Sangyong Jung, Sunny Hei Wong, Nguan Soon Tan, Nanwei Tong, Guy A Rutter, Markus R Wenk, David L Silver, Per-Olof Berggren, Yusuf Ali

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Abstract

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 β 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 β cell LD numbers, lowered β cell ATP levels, reduced Ca 2+ signaling, dampened vesicle exocytosis, down-regulated β 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 β 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 β cell lipotoxicity.

Original languageEnglish
Article numbere2113074119
Pages (from-to)1-10
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number11
DOIs
Publication statusPublished - 15 Mar 2022

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. The mouse pancreatic β cell line MIN6 was kindly provided by Dr. Jun-ichi Miyazaki, Osaka University, Japan. This work was supported by the Singapore Ministry of Education grants under its Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2015-T2-2-087 and MOE2018-T2-1-085 to Y.A.) and Tier 1 (2017-T1-001-220 and 2019-T1-001-059 to Y.A.); the LKCMedicine, Nanyang Technological University Singapore Start-up Grant (P.-O.B.); and the LKCMedicine Healthcare Research Fund (Diabetes Research), established through the generous support of alumni of Nanyang Technological University, Singapore (Y.A.). Q.W.C.H. is supported by the Nanyang President’s Graduate Scholarship award, Nanyang Technological University, Singapore. J.N.F. is supported by Singapore National Research Foundation Fellowship award (NRF-NRFF2016-03). Work in the M.R.W. and F.T. laboratories is supported by grants from the National University of Singapore via the Life Sciences Institute, the National Research Foundation (NRF; NRFI2015-05 and NRFSBP-P4) and the NRF and Agency for Science, Technology and Research (A*STAR) Industry Alignment Fund–Industry Collaborative Project I1901E0040. N.T. is supported by the 1.3.5 Project for Disciplines of Excellence grant, West China Hospital, Sichuan University (ZYGD18017). P.-O.B. is supported by the grants from the Swedish Research Council, the Family Erling-Persson Foundation, the Novo Nordisk Foundation, the Stichting af Jochnick Foundation, the Swedish Diabetes Association, the Scandia Insurance Company Ltd., the Diabetes Research and Wellness Foundation, Berth von Kantzow’s Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the ERC-2018-AdG 834860 EYELETS, and the Center of Excellence–International Collaboration Initiative Grant (139180012, China). X.Z. is currently supported by the National Natural Science Foundation of China grant (82070846). G.A.R. was supported by the Wellcome Trust Investigator

Funding Information:
(WT212625/Z/18/Z) Award, the Medical Research Council Programme grant (MR/R022259/1), and the European Union Horizon2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 115881 (RHAPSODY). We thank the A*STAR Microscopy Platform (Singapore) for the electron microscopy support and analysis.

Funding Information:
Competing interest statement: G.A.R. has received grant funding from Les Laboratoires Servier and from Sun Pharmaceuticals and is a consultant for Sun Pharmaceuticals. P.-O.B. is the founder of Biocrine AB and is also the CEO of this company.

Funding Information:
The mouse pancreatic β cell line MIN6 was kindly provided by Dr. Jun-ichi Miyazaki, Osaka University, Japan. This work was supported by the Singapore Ministry of Education grants under its Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2015-T2-2-087 and MOE2018-T2-1-085 to Y.A.) and Tier 1 (2017-T1-001-220 and 2019-T1-001-059 to Y.A.); the LKCMedicine, Nanyang Technological University Singapore Start-up Grant (P.-O.B.); and the LKCMedicine Healthcare Research Fund (Diabetes Research), established through the generous support of alumni of Nanyang Technological University, Singapore (Y.A.). Q.W.C.H. is supported by the Nanyang President's Graduate Scholarship award, Nanyang Technological University, Singapore. J.N.F. is supported by Singapore National Research Foundation Fellowship award (NRF-NRFF2016-03). Work in the M.R.W. and F.T. laboratories is supported by grants from the National University of Singapore via the Life Sciences Institute, the National Research Foundation (NRF; NRFI2015-05 and NRFSBP-P4) and the NRF and Agency for Science, Technology and Research (A*STAR) Industry Alignment Fund-Industry Collaborative Project I1901E0040. N.T. is supported by the 1.3.5 Project for Disciplines of Excellence grant, West China Hospital, Sichuan University (ZYGD18017). P.-O.B. is supported by the grants from the Swedish Research Council, the Family Erling-Persson Foundation, the Novo Nordisk Foundation, the Stichting af Jochnick Foundation, the Swedish Diabetes Association, the Scandia Insurance Company Ltd., the Diabetes Research and Wellness Foundation, Berth von Kantzow's Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the ERC-2018-AdG 834860 EYELETS, and the Center of Excellence-International Collaboration Initiative Grant (139180012, China). X.Z. is currently supported by the National Natural Science Foundation of China grant (82070846). G.A.R. was supported by the Wellcome Trust Investigator (WT212625/Z/18/Z) Award, the Medical Research Council Programme grant (MR/R022259/1), and the European Union Horizon2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 115881 (RHAPSODY). We thank the A*STAR Microscopy Platform (Singapore) for the electron microscopy support and analysis.

Publisher Copyright:
Copyright © 2022 the Author(s)

Keywords

  • FIT2
  • lipid droplets
  • pancreatic β cells
  • ER stress
  • diet-induced diabetes

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