{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:36:30Z","timestamp":1791041790422,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T00:00:00Z","timestamp":1724716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["21K08531"],"award-info":[{"award-number":["21K08531"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["21K16342"],"award-info":[{"award-number":["21K16342"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Dysfunction or loss of pancreatic \u03b2 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 \u03b2 cell lipotoxicity, resulting in abnormal insulin synthesis and secretion. Increased glutamate release can cause glucotoxicity in \u03b2 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 \u03b2 cells and emphasizing the importance of investigating the role of NMDA in \u03b2 cell dysfunction.<\/jats:p>","DOI":"10.3390\/nu16172865","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T06:19:01Z","timestamp":1724739541000},"page":"2865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NMDA Suppresses Pancreatic ABCA1 Expression through the MEK\/ERK\/LXR Pathway in Pancreatic Beta Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8909-9821","authenticated-orcid":false,"given":"Takanobu","family":"Saheki","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Imachi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0012-5263","authenticated-orcid":false,"given":"Kensaku","family":"Fukunaga","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seisuke","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Saheki","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7335-7196","authenticated-orcid":false,"given":"Koji","family":"Murao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,27]]},"reference":[{"key":"ref_1","first-page":"1584","article-title":"Long Term Exposure to Fatty Acids and Ketones Inhibits B-Cell Functions in Human Pancreatic Islets of Langerhans","volume":"80","author":"Zhou","year":"1995","journal-title":"J. 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