The regeneration of β-cell mass and preservation of its endocrine function under lipotoxicity are long-sought goals in diabetes research. Membrane protein caveolin-1 (Cav-1) is related to 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 investigate the related mechanisms. Here, we found that Cav-1 silencing significantly promoted β-cell proliferation, inhibited palmitate (PA)-induced apoptosis and enhanced insulin production and secretion. These effects were associated with enhanced phosphorylation of Akt and ERK1/2 protein, which then downregulated the expression of cell cycle inhibitors (FOXO1, GSK3β, P21, P27 and P53) and upregulated Cyclin D2 and Cyclin D3 expression. Subsequent inhibition of PI3K/Akt and ERK/MAPK pathways abolished Cav-1 depletion induced β-cell mass protection. Furthermore,under PA enhanced endoplasmic reticulum (ER) stress, Cav-1 silencing significantly reduced eIF2α phosphorylation and expression of ER stress-responsive markers BiP and CHOP, which mediated the sensitization to lipotoxicity. Our findings suggest the potential application of the Cav-1 molecule as a target for effective T2DM treatment through preservation of lipotoxicity-induced β-cell dysfunction and mass reduction.
Disclosure
W. Zeng: None. K. Liu: None. J. Tang: None. H. Li: None. H. Xu: None. H. Lu: None. H. Peng: None. C. Lin: None. R. Gao: None. S. Lin: None. K. Lin: None. Y. Jiang: None. L. Zeng: None.
