{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:20:43Z","timestamp":1788344443917,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"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":["JP26K19537"],"award-info":[{"award-number":["JP26K19537"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Pancreatic \u03b2 cells require tightly controlled cholesterol distribution to maintain glucose sensing, insulin-granule trafficking, and regulated exocytosis. ATP-binding cassette transporter A1 (ABCA1) exports cellular cholesterol and phospholipids to lipid-poor apolipoprotein A-I and is a central component of \u03b2-cell cholesterol homeostasis. \u03b2-cell-specific Abca1 deletion causes cholesterol accumulation and impaired glucose-stimulated insulin secretion, whereas human studies of rare ABCA1 loss-of-function mutations have reported heterogeneous secretory phenotypes. Endocrine, metabolic, inflammatory, lipoprotein, and post-transcriptional signals regulate pancreatic ABCA1. Exendin-4 activates CaMKK\/CaMKIV\/PREB-dependent transcription, insulin-like growth factor-1 acts through PI3K\/Akt\/FoxO1 signaling, and pemafibrate increases ABCA1 through PPAR-\u03b1-dependent regulation in experimental models. Conversely, angiotensin II, tumor necrosis factor-\u03b1, oxidized low-density lipoprotein, and N-methyl-D-aspartate suppress ABCA1 through distinct or partially convergent pathways, while miR-33a directly suppresses ABCA1 in human and mouse islets. \u03b2-cell function depends on the balance among LDLR-dependent cholesterol uptake, PCSK9-mediated receptor regulation, intracellular sterol trafficking and esterification, ABCG1-dependent handling, and ABCA1-dependent export rather than on total cellular cholesterol alone. Although several regulator-specific mechanisms remain preclinical and await independent replication, this review integrates these pathways and discusses their nutritional and translational relevance in type 2 diabetes.<\/jats:p>","DOI":"10.3390\/nu18172879","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:02:52Z","timestamp":1788343372000},"page":"2879","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ABCA1 as a Gatekeeper of Pancreatic \u03b2-Cell Cholesterol Homeostasis: Links Between Lipoprotein Stress, Lipotoxicity, and Insulin Secretion"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0012-5263","authenticated-orcid":false,"given":"Kensaku","family":"Fukunaga","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun 761-0793, Kagawa, 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, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8909-9821","authenticated-orcid":false,"given":"Takanobu","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, Kagawa, 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, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8046-6756","authenticated-orcid":false,"given":"Wenyi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun 761-0793, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun 761-0793, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2998-2448","authenticated-orcid":false,"given":"Rathana","family":"Ly","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun 761-0793, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marino","family":"Kumano","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun 761-0793, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun 761-0793, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2179-5039","authenticated-orcid":false,"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, Kagawa, 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, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Galli, A., Arunagiri, A., Dule, N., Castagna, M., Marciani, P., and Perego, C. 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