Format

Send to

Choose Destination
Cell Signal. 2014 Feb;26(2):268-78. doi: 10.1016/j.cellsig.2013.11.019. Epub 2013 Nov 21.

Activation of PPARβ/δ protects pancreatic β cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor.

Author information

1
Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
2
West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
3
Laboratory of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
4
Laboratory of Transplantation Engineering, West China Hospital of Sichuan University, Chengdu, China.
5
Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China. Electronic address: buddyjun@hotmail.com.

Abstract

We previously showed that activated peroxisome proliferator-activated receptor (PPAR)β/δ can protect pancreatic β cells against lipotoxic apoptosis. However, the molecular mechanism remained unclear. Glucagon-like peptide-1 receptor (GLP-1R) has been reported to exhibit a protective effect against lipotoxic apoptosis in pancreatic β cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPARβ/δ activation suppressed apoptosis and improved β cell function impaired by fatty acids, focusing on contribution of GLP-1R. Isolated rat islets and rat insulin-secreting INS-1 cells were treated with the PPARβ/δ agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPARβ/δ or treated with the PPARβ/δ antagonist GSK0660. Apoptosis was assessed by DNA fragmentation, Hoechst 33342 staining and flow cytometry. GLP-1R expression in INS-1 cells and islets was assayed by immunoblotting, quantitative PCR (qPCR) and immunofluorescence staining. SREBP-1c, Caveolin-1, Akt, Bcl-2, Bcl-xl and caspase-3 expression was measured using immunoblotting and qPCR. Our results showed that PPARβ/δ activation decreased apoptosis in β cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucose-stimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in β cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPARβ/δ-regulated GLP-1R expression. Finally, GW exerted anti-apoptotic effects via interfering with GLP-1R-dependent Akt/Bcl-2 and Bcl-xl/caspase-3 signaling pathways. Our study suggested that the anti-apoptotic action of GW may involve its transcriptional regulation of GLP-1R, and PPARβ/δ activation may represent a new therapeutic method for protecting pancreatic β cells from lipotoxicity.

KEYWORDS:

Apoptosis; ELISA; Ex; FBS; FDA; FFA; FITC; G protein coupled receptor; GLP-1R; GPCR; GSIS; GW; GW501516; HBSS; Hanks' balanced salt solution; KRBH; PA; PI; PPARβ/δ; Palmitate; Pancreatic β cells; SREBP-1c; T2D; enzyme-linked immunosorbent assay; exendin-4; fetal bovine serum; fluorescein diacetate; fluorescein isothiocyanate; free fatty acid; glucagon-like peptide-1 receptor; glucose-free Krebs–Ringer bicarbonate HEPES buffer; glucose-stimulated insulin secretion; palmitate; peroxisome proliferator-activated receptor β/δ; propidium iodide; qPCR; quantitative polymerase chain reaction; sterol regulatory element binding protein-1c; type 2 diabetes

PMID:
24269940
DOI:
10.1016/j.cellsig.2013.11.019
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center