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NMDA Suppresses Pancreatic ABCA1 Expression through the MEK/ERK/LXR Pathway in Pancreatic Beta Cells.
- Source :
-
Nutrients [Nutrients] 2024 Aug 27; Vol. 16 (17). Date of Electronic Publication: 2024 Aug 27. - Publication Year :
- 2024
-
Abstract
- Dysfunction or loss of pancreatic β cells can cause insulin deficiency and impaired glucose regulation, resulting in conditions like type 2 diabetes. The ATP-binding cassette transporter A1 (ABCA1) plays a key role in the reverse cholesterol transport system, and its decreased expression is associated with pancreatic β cell lipotoxicity, resulting in abnormal insulin synthesis and secretion. Increased glutamate release can cause glucotoxicity in β cells, though the detailed mechanisms remain unclear. This study investigated the effect of N-methyl-D-aspartic acid (NMDA) on ABCA1 expression in INS-1 cells and primary pancreatic islets to elucidate the signaling mechanisms that suppress insulin secretion. Using Western blotting, microscopy, and biochemical analyses, we found that NMDA activated the mitogen-activated protein kinase (MEK)-dependent pathway, suppressing ABCA1 protein and mRNA expression. The MEK-specific inhibitor PD98059 restored ABCA1 promoter activity, indicating the involvement of the extracellular signal-regulated kinase (MEK/ERK) pathway. Furthermore, we identified the liver X receptor (LXR) as an effector transcription factor in NMDA regulation of ABCA1 transcription. NMDA treatment increased cholesterol and triglyceride levels while decreasing insulin secretion, even under high-glucose conditions. These effects were abrogated by treatment with PD98059. This study reveals that NMDA suppresses ABCA1 expression via the MEK/ERK/LXR pathway, providing new insights into the pathological suppression of insulin secretion in pancreatic β cells and emphasizing the importance of investigating the role of NMDA in β cell dysfunction.
- Subjects :
- Animals
Rats
Cholesterol metabolism
Insulin metabolism
Insulin Secretion drug effects
Male
Extracellular Signal-Regulated MAP Kinases metabolism
Cell Line
Insulin-Secreting Cells metabolism
Insulin-Secreting Cells drug effects
ATP Binding Cassette Transporter 1 metabolism
ATP Binding Cassette Transporter 1 genetics
N-Methylaspartate pharmacology
Liver X Receptors metabolism
MAP Kinase Signaling System drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2072-6643
- Volume :
- 16
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Nutrients
- Publication Type :
- Academic Journal
- Accession number :
- 39275180
- Full Text :
- https://doi.org/10.3390/nu16172865