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Cited by 48Pancreatic function and diabetesLipid metabolism and biosynthesisEndoplasmic Reticulum Stress and Disease

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

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Zheng, Xiaofeng, Ho, Qing Wei Calvin, Chua, Minni, Stelmashenko, Olga, Yeo, Xin Yi, Muralidharan, Sneha, Torta, Federico, Chew, Elaine Guo Yan +11 more·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2113074119PMC PMC8931238
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Abstract

Significance: With obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage–inducing transmembrane protein 2 (FIT2)–facilitated, pancreatic β cell LD biogenesis, which in turn induces β cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)–associated degradation. Loss of β cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.

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  • In vivo loss of FIT2 in adipocytes and pancreatic β cells results in failed lipid droplet formation.

    “The in vivo loss of FIT2 in adipocytes and pancreatic β cells also resulted in failed LD formation (24, 59).”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [59]

    The Results section (“Palmitate and Stearate Reduce β Cell FIT2 Protein Levels”; page not provided) reports that β-cell-specific FIT2 deletion in mice significantly reduced lipid droplet numbers in islets. It does not show that droplet formation failed altogether. The adipocyte portion of the sentence has another citation; this paper’s experiment concerns β cells. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Zheng, X., Ho, Q. W. C., Chua, M., Stelmashenko, O., Yeo, X. Y., Muralidharan, S., Torta, F., Chew, E. G. Y., Lian, M. M., Foo, J. N., Jung, S., Wong, S. H., Tan, N. S., Tong, N., Rutter, G. A., Wenk, M. R., Silver, D. L., Berggren, P.-O., & Ali, Y.
Affiliations
  • Nanyang Technological University (SG)
  • Agency for Science, Technology and Research (SG)
  • National University of Singapore (SG)
  • Sichuan University (CN)
  • Karolinska University Hospital (SE)
Corresponding author
Ali, Yusuf
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-03-07
Volume
119
Issue
11
Pages
e2113074119-e2113074119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2113074119
PMC
PMC8931238
OpenAlex
W4220954100
Cited by
48
References
4
Citations by year
2026: 7 · 2025: 8 · 2024: 21 · 2023: 6 · 2022: 6
FWCI
10.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
  • Ulster University Research Portal (Ulster University) (submittedVersion, cc-by)
Funders
  • Ministry of Education - Singapore (MOE2015-T2-2-087, MOE2018-T2-1-085, 2017-T1-001-220, 2019-T1-001-059)
  • Nanyang Technological University (LKCMedicine Healthcare Research Fund (Diabetes Research), Nanyang President''''s Graduate Scholarship)
  • National Research Foundation Singapore (NRF-NRFF2016-03, NRFI2015-05, NRFSBP-P4, IAF-ICP I1901E0040)
  • Project for Disciplines of Excellence West China Hospital (ZYGD18017)
  • ERC-2018-AdG (834860 EYELETS)
  • National Natural Science Foundation of China (82070846)
  • Center of Excellence-International Collaboration Initiative Grant China (139180012)
  • Wellcome (Wellcome Trust Investigator (WT212625/Z/18/Z) Award)
  • RCUK | Medical Research Council (MR/R022259/1)
  • EC | Horizon 2020 (No 115881 (RHAPSODY))
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
saturated fatty acids, lipid droplets, pancreatic beta cells, endoplasmic reticulum stress, ER-associated degradation, ceramide, insulin secretion, beta-cell death, diet-induced diabetes, obesity, palmitate, stearate, unsaturated fatty acids, protein acylation, lipid droplet formation
MeSH terms
Animals, Cell Line, Diabetes Mellitus, Fatty Acids, Glucose, Membrane Proteins, Mutation, Palmitates, Stearates, Glucose Intolerance, Lipid Metabolism, Insulin-Secreting Cells, Mice, Endoplasmic Reticulum Stress, Lipid Droplets

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