Abstract
Progressive pancreatic β cell failure underlies the transition of impaired glucose tolerance to overt diabetes; endoplasmic reticulum (ER) stress expedites β cell failure in this situation. ER stress can be elicited by lipotoxicity and an increased demand for insulin in diabetes. We previously reported that the lipid droplet protein perilipin 2 (PLIN2) modulates lipid homeostasis in the liver. Here, we show that PLIN2 modulates the unfolded protein response (UPR) and ER stress in pancreatic β cells. PLIN2 expression goes up when β cells are exposed to a lipid load or to chemical ER stress inducers. Downregulation of PLIN2 ameliorates the effects of fatty acid-and chemical-induced ER stress, whereas PLIN2 overexpression exacerbates them. Diabetic Akita mice, which carry a heterozygous C96Y Ins2 mutation, exhibit elevated PLIN2 expression and ER stress in their β cells. Genetic ablation of Plin2 in Akita mice leads to mitigation of ER stress, forestalling β cell apoptosis, partially restoring β cell mass, and ameliorating diabetes. Mechanistic experiments showed that PLIN2 downregulation is associated with enhanced autophagic flux and accelerated ER stress resolution. In sum, we have identified a crucial role for PLIN2 in modulating autophagy, ER stress resolution, and β cell apoptosis and survival.
Original language | English (US) |
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Article number | 40855 |
Journal | Scientific reports |
Volume | 7 |
DOIs | |
State | Published - Jan 19 2017 |
Externally published | Yes |
ASJC Scopus subject areas
- General