Preprint
Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets
bioRxiv
Cold Spring Harbor Laboratory Press
11/18/2024
DOI: 10.1101/2024.11.17.624030
PMCID: PMC11601606
PMID: 39605485
Abstract
Knockdown (KD) of lipid droplet (LD) protein perilipin 2 (PLIN2) in beta cells impairs glucose-stimulated insulin secretion (GSIS) and mitochondrial function. Here, we addressed a pathway responsible for compromised mitochondrial integrity in PLIN2 KD beta cells. In PLIN2 KD human islets, mitochondria were fragmented in beta cells but not in alpha cells. Glucagon but not insulin level was elevated. While the formation of early LDs followed by fluorescent fatty acids (FA) analog Bodipy C12 (C12) was preserved, C12 accumulated in mitochondria over time in PLIN2 KD INS-1 cells. A lysosomal acid lipase inhibitor Lali2 prevented C12 transfer to mitochondria, mitochondrial fragmentation, and the impairment of GSIS. Direct interactions between LD-lysosome and lysosome-mitochondria were increased in PLIN2 KD INS-1 cells. Thus, FA released from LDs by microlipophagy cause mitochondrial changes and impair GSIS in PLIN2 KD beta cells. Interestingly, glucolipotoxic condition (GLT) caused C12 accumulation and mitochondrial fragmentation similar to PLIN2 KD in beta cells. Moreover, Lali2 reversed mitochondrial fragmentation and improved GSIS in human islets under GLT. In summary, PLIN2 regulates microlipophagy to prevent excess FA flux to mitochondria in beta cells. This pathway also contributes to GSIS impairment when LD pool expands under nutrient load in beta cells.Competing Interest StatementThe authors have declared no competing interest.
Details
- Title: Subtitle
- Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets
- Creators
- Siming Liu - University of IowaIsrael Wipf - University of IowaAditya Joglekar - University of IowaAidan Freshly - University of IowaCorinne Bovee - University of IowaLucy Kim - University of IowaSyreine Richtsmeier - University of IowaSpencer Peachee - University of IowaShayla Kopriva - University of IowaAnamika Vikram - University of IowaDalal El Ladiki - University of Iowa, Internal MedicineFatma Ilerisoy - University of IowaBeyza Ilerisoy - University of IowaGianna Sagona - University of IowaClaudia Jun - University of IowaMichelle Giedt - University of IowaTina Tootle - University of IowaJames Ankrum - University of IowaYumi Imai - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.1101/2024.11.17.624030
- PMID
- 39605485
- PMCID
- PMC11601606
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory Press; Cold Spring Harbor
- Language
- English
- Date posted
- 11/18/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Biology; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984751756602771
Metrics
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