ABCA1 as a Gatekeeper of Pancreatic β-Cell Cholesterol Homeostasis: Links Between Lipoprotein Stress, Lipotoxicity, and Insulin Secretion

Abstract

Pancreatic β 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 β-cell cholesterol homeostasis. β-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-α-dependent regulation in experimental models. Conversely, angiotensin II, tumor necrosis factor-α, 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. β-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.