Urolithin A, a pomegranate metabolite, protects pancreatic β cells from apoptosis by activating autophagy

Urolithin A is an active metabolite of plant polyphenol ellagic acid generated by intestinal flora, which is derived from strawberry or traditional anti-diabetic Chinese medicine such as Punica granatum L. and Phyllanthus emblica. The present study aimed to whether urolithin A can protect against glycolipid-toxicity-induced apoptosis of pancreatic β-cells and the underlying mechanisms. Apoptosis was induced in the pancreas of mice with type 2 diabetes and MIN6 pancreatic β-cells. CC-8 assay was conducted to determine cell viability. Flow cytometry, JC-1 fluorescent probe, and western blot assays were performed to assess apoptosis. Immunofluorescence and western blot assays were used to detect changes in autophagy. The mechanism of apoptosis was elucidated using autophagy inhibitor chloroquine. Urolithin A intervention significantly reduced pancreatic cell apoptosis in diabetic mice and MIN6 β cells. This was achieved by the downregulation of cleaved-caspase 3, cleaved-caspase 1, and restoration of cell viability, cell morphology and mitochondrial membrane potential, accompanied with the downregulation of autophagic protein SQSTM1/p62 and upregulation of LC3II. Chloroquine, an autophagy inhibitor, reversed the anti-glucolipotoxic and anti-apoptotic effects of urolithin A. These findings suggest that urolithin A protects against glucolipotoxicity-induced apoptosis in pancreatic β-cells by inducing activation of autophagy. Glucolipotoxicity causes mitochondrial damage (decreased mitochondrial membrane potentialΔΨm, caspase 3 cleavage) and defective autophagy, which contributes to the apoptosis of β cells in type 2 diabetes. Urolithin A, intestinal microflora metabolite of ellagic acid that occur in Pomegranate (Punica granatum L.),Emblica officinalis(Phyllanthus emblica Linn), improves the impaired mitochondrial membrane potential and autophagic flux, inhibits caspase activation, reduces glucolipotoxicity-induced pancreatic β-cell apoptosis [Display omitted] .