Biology subjects

Freshly, A.

Publications and source records attributed to Freshly, A..

2 recordsLinked to original sources

bioRxiv2025

ALPHA/BETA HYDROLASE DOMAIN CONTAINING 5 SUPPORTS GLUCOSE-STIMULATED-LIPOLYSIS AND INSULIN SECRETION IN PANCREATIC BETA CELLS

PNPLA2 (aka adipose triglyceride lipase) is the rate limiting enzyme of triglyceride (TG) catabolism at the surface of lipid droplets (LDs). Lipolysis by PNPLA2 increases with glucose in pancreatic beta cells and produces metabolites that support glucose-stimulated insulin secretion (GSIS). Upregulation of lipolysis by glucose is blunted in human islets affected by type 2 diabetes. Here, we aim to determine how glucose regulates lipolysis in beta cells. We found that glucose recruits alpha/beta hydrolase domain containing 5 (ABHD5), a co-activator of PNPLA2 to LDs where lipolysis occurs. ABHD5 recruitment to LDs was reduced by the addition of H-89 and the expression of a mutant ABHD5 that is resistant to phosphorylation by a cAMP dependent kinase (PKA) indicating partial dependence of recruitment on PKA. Importantly, ABHD5 was indispensable for glucose responsiveness of lipolysis in INS-1 832/13 (INS-1) cells. Downregulation of ABHD5 increased LDs and TG content in INS-1 cells and human islets indicating that ABHD5 is highly active in beta cells. Additionally, glucose-stimulated insulin secretion was impaired in ABHD5 downregulated INS-1 and human pseudoislets, which agrees with impaired GSIS in ATGL downregulated beta cells. Thus, ABHD5 plays an important role in conferring glucose responsiveness of lipolysis and supporting insulin secretion in beta cells.

cell biology↗

bioRxiv2024

Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets

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.

molecular biology↗