Lipotoxicity leads to insulin secretion deficiency, which is among the important causes for the onset of type 2 diabetes mellitus. Thus, the restoration of β-cell mass and preservation of its endocrine function are long-sought goals in diabetes research. Previous studies have suggested that the membrane protein caveolin-1 (Cav-1) is implicated in β-cell apoptosis and insulin secretion, however, the underlying mechanisms still remains unclear. Our objective is to explore whether Cav-1 depletion protects pancreatic β cells from lipotoxicity and what are the underlying mechanisms. In this study, we found that Cav-1 silencing significantly promoted β-cell proliferation, inhibited palmitate (PA)-induced pancreatic β-cell apoptosis and enhanced insulin production and secretion. These effects were associated with enhanced activities of Akt and ERK1/2, which in turn downregulated the expression of cell cycle inhibitors (FOXO1, GSK3β, P21, P27 and P53) and upregulated the expression of Cyclin D2 and Cyclin D3. Subsequent inhibition of PI3K/Akt and ERK/MAPK pathways abolished Cav-1 depletion induced β-cell mass protection. Furthermore, under PA induced endoplasmic reticulum (ER) stress, Cav-1 silencing significantly reduced eIF2α phosphorylation and the expression of ER stress-responsive markers BiP and CHOP, which are among the known sensitizers of lipotoxicity. Our findings suggest Cav-1 as potential target molecule in T2DM treatment via the preservation of lipotoxicity-induced β-cell mass reduction and the attenuation of insulin secretion dysfunction.

脂中毒导致胰岛素分泌不足，这是2型糖尿病发作的重要原因之一。因此，β细胞团的恢复及其内分泌功能的保持是糖尿病研究的长期目标。先前的研究表明，膜蛋白小窝蛋白1（Cav-1）与β细胞凋亡和胰岛素分泌有关，但是，其潜在机制仍不清楚。我们的目标是探讨Cav-1耗竭是否能保护胰腺β细胞免于脂毒性以及其潜在机制是什么。在这项研究中，我们发现Cav-1沉默可显着促进β细胞增殖，抑制棕榈酸酯（PA）诱导的胰腺β细胞凋亡并增强胰岛素产生和分泌。这些效应与Akt和ERK1 / 2的活性增强有关，进而下调细胞周期抑制剂（FOXO1，GSK3β，P21，P27和P53）的表达，并上调Cyclin D2和Cyclin D3的表达。随后抑制PI3K / Akt和ERK / MAPK途径废除了Cav-1耗竭诱导的β细胞大规模保护。此外，在PA诱导的内质网（ER）胁迫下，Cav-1沉默显着降低eIF2α磷酸化以及ER应激反应标记BiP和CHOP的表达，这是已知的脂毒性敏化剂。我们的发现表明Cav-1是T2DM治疗中潜在的靶分子 随后抑制PI3K / Akt和ERK / MAPK途径废除了Cav-1耗竭诱导的β细胞大规模保护。此外，在PA诱导的内质网（ER）胁迫下，Cav-1沉默显着降低eIF2α磷酸化以及ER应激反应标记BiP和CHOP的表达，这是已知的脂毒性敏化剂。我们的发现表明Cav-1是T2DM治疗中潜在的靶分子 随后抑制PI3K / Akt和ERK / MAPK途径废除了Cav-1耗竭诱导的β细胞大规模保护。此外，在PA诱导的内质网（ER）胁迫下，Cav-1沉默显着降低eIF2α磷酸化以及ER应激反应标记BiP和CHOP的表达，这是已知的脂毒性敏化剂。我们的发现表明Cav-1是T2DM治疗中潜在的靶分子通过保持脂毒性诱导的β细胞质量减少和减轻胰岛素分泌功能障碍。