Abstract
BackgroundChronic exposure of pancreatic β-cells to excess free fatty acids is thought to contribute to type 2 diabetes pathogenesis in obesity by impairing β-cell function and even leading to apoptosis. In β-cells, lipid droplet-associated protein perilipin 5 (PLIN5) has been shown to enhance insulin secretion by regulating intracellular lipid metabolism; the roles of PLIN5 in response to lipotoxicity remain poorly understood.MethodsINS-1 β-cells were transfected with PLIN5-overexpression adenovirus (Ad-PLIN5) and treated with palmitate. C57BL/6 J male mice were fed with high fat diet and tail intravenous injected with adeno-associated virus overexpressing PLIN5 (AAV-PLIN5) in β-cells.ResultsOur data showed that palmitate and PPAR agonists including WY14643 (PPARα), GW501516 (PPARβ/δ), rosiglitazone (PPARγ) in vitro all induced PLIN5 expression in INS-1 cells. Under palmitate overload, although upregulating PLIN5 promoted lipid droplet storage, it alleviated lipotoxicity in INS-1 β-cells with improved cell viability, cell apoptosis and β-cell function. The protection role of PLIN5 in β-cell function observed in cell experiments were further verified in in vivo study indicated by mitigated glucose intolerance in high fat diet fed mice with β-cell-specific overexpression of PLIN5. Mechanistic experiments revealed that enhanced FAO induced by elevation of PLIN5, followed by decreased ER stress may be a major mechanism responsible for alleviation of lipotoxicity observed in the present study.ConclusionsOur finding substantiated the important role of PLIN5 in protection against lipotoxicity in β-cells.
Highlights
Chronic exposure of pancreatic β-cells to excess free fatty acids is thought to contribute to type 2 diabetes pathogenesis in obesity by impairing β-cell function and even leading to apoptosis
chow diet (CHOW) mice were injected with saline as the control group. 1 week after injection, fasting (12 h) and fed glucose (2 h) levels were determined from tail vein blood with a glucometer (FreeStyle, Alameda, CA, USA). 10–14 days after injection, glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were conducted
There was a significant upregulation in perilipin 5 (PLIN5) protein level among high fat diet (HFD) mice and ob/ob mice the serum free fatty acids (FFA) level was comparable in CHOW group and HFD group (Fig. 1a, b)
Summary
Chronic exposure of pancreatic β-cells to excess free fatty acids is thought to contribute to type 2 diabetes pathogenesis in obesity by impairing β-cell function and even leading to apoptosis. In β-cells, lipid droplet-associated protein perilipin 5 (PLIN5) has been shown to enhance insulin secretion by regulating intracellular lipid metabolism; the roles of PLIN5 in response to lipotoxicity remain poorly understood. Chronic exposure of pancreatic β-cell to free fatty acids (FFA), accompanied with obesity, may impair insulin secretion and lead to β-cell apoptosis in vivo and ex vivo, a phenomenon termed “lipotoxicity” [2, 3]. LD act as a fuel supplier during periods of energy needs and a lipolytic barrier to avoid cellular lipotoxicity by regulating LD lipolysis and plays a critical role in maintaining lipid metabolism homeostasis and this metabolic regulation of LD was mediated by LD-associated proteins [13, 14]
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