4.7 Article

Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes

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DIABETES
卷 70, 期 11, 页码 2595-2607

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AMER DIABETES ASSOC
DOI: 10.2337/db21-0261

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  1. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK090570, DK050203, DK126482]
  2. Vanderbilt Diabetes Research and Training Center [DK20593]
  3. JDRF fellowship [3-PDF-2019-738-A-N]

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The accumulation of lipid droplets (LDs) in human pancreatic islets, mainly observed after 11 years of age, is essential for adult human islet beta-cell activity by preserving free fatty acid (FFA) homeostasis. Manipulating the levels of perilipin 2 (PLIN2), a key LD scaffold protein, can influence insulin secretion and beta-cell function in human islet cells. These findings suggest that LDs play a crucial role in maintaining beta-cell activity in adult human islets.
Free fatty acids (FFAs) are often stored in lipid droplet (LD) depots for eventual metabolic and/or synthetic use in many cell types, such a muscle, liver, and fat. In pancreatic islets, overt LD accumulation was detected in humans but not mice. LD buildup in islets was principally observed after roughly 11 years of age, increasing throughout adulthood under physiologic conditions, and also enriched in type 2 diabetes. To obtain insight into the role of LDs in human islet beta -cell function, the levels of a key LD scaffold protein, perilipin 2 (PLIN2), were manipulated by lentiviral-mediated knockdown (KD) or overexpression (OE) in EndoC beta H2-Cre cells, a human cell line with adult islet beta -like properties. Glucose-stimulated insulin secretion was blunted in PLIN2KD cells and improved in PLIN2OE cells. An unbiased transcriptomic analysis revealed that limiting LD formation induced effectors of endoplasmic reticulum (ER) stress that compromised the expression of critical beta -cell function and identity genes. These changes were essentially reversed by PLIN2OE or using the ER stress inhibitor, tauroursodeoxycholic acid. These results strongly suggest that LDs are essential for adult human islet beta -cell activity by preserving FFA homeostasis.

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