PLIN2 is a Key Regulator of the Unfolded Protein Response and Endoplasmic Reticulum Stress Resolution in Pancreatic β Cells

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.

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

“…; Chen et al . ), both of which can influence hepatic lipid accumulation. Thus, additional studies of the effects of hepatic Plin2 expression on the levels and activities of hepatic DNL enzymes and lipid flux (Lambert et al .…”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…133 To test whether PLIN2 protects beta cells from the cytotoxic effect of chronic lipid overload, PLIN2 was downregulated by shRNA in RINm5F and INS1 cells; 138 the reduction did not exacerbate or prevent cell death under chronic lipid overload, indicating that PLIN2 and LD formation have little effect on cell viability under lipotoxic stress in these beta cell lines. 137 Whole-body PLIN2 deficiency in Akita mice improved blood glucose levels compared with PLIN2-sufficient Akita mice, indicating that the loss of PLIN2 reduces ER stress in beta cells. 138 The role of PLIN2 in beta cells under ER stress was studied using Akita mice that develop marked ER stress due to an insulin 2 gene mutation.…”

“…123 In nonbeta cells, the modulation of PLIN2 expression is reported to affect multiple aspects of cellular lipid handling, including FA uptake, beta-oxidation, and activation of nuclear receptors in the liver, heart, macrophages, and white adipocytes. 133,137 In MIN6 cells, the reduction of PLIN2 by antisense oligo nucleotide (ASO) significantly reduced TG contents, FA uptake, and FA oxidation indicating that PLIN2 in beta cells regulates lipid metabolism as well. PLIN2 protein is increased in beta cell lines, mouse islets, and human islets after fatty acid loading in vitro and in islets from obese mice (high-fat diet, ob/ob mice) and fasted mice.…”

“…138 However, the impact of PLIN2 reduction for beta cell function under lipotoxic stress was not studied. 137 In the study, the authors propose that the loss of PLIN2 reduces ER stress by upregulating autopahgy. 137 Whole-body PLIN2 deficiency in Akita mice improved blood glucose levels compared with PLIN2-sufficient Akita mice, indicating that the loss of PLIN2 reduces ER stress in beta cells.…”

“…138 The role of PLIN2 in beta cells under ER stress was studied using Akita mice that develop marked ER stress due to an insulin 2 gene mutation. 137 Future work will be important to determine whether the loss of PLIN2 positively or negatively affects beta cell function in vivo under other stresses, especially overnutrition, considering that LD are reported to protect or exacerbate stress responses depending on type of stress. 137 In the study, the authors propose that the loss of PLIN2 reduces ER stress by upregulating autopahgy.…”