Targeting PGC-1α to Overcome the Harmful Effects of Glucocorticoids in Porcine Neonatal Pancreas Cell Clusters

다국어 초록 (Multilingual Abstract)

BACKGROUND: Peroxisome proliferator-activated receptor gamma-coactivator-1α (PGC-1α) has recently been implicated as a crucial factor in the glucocorticoid-suppressed expansion and transdifferentiation of porcine neonatal pancreatic cell clusters (NPCCs). However, the molecular mechanism has not been clarified. METHODS: We investigated whether the suppression of PGC-1α expression protects against &bgr;-cell dysfunction induced by dexamethasone (Dx) treatment in vitro and in vivo and determined the mechanism of action of PGC-1α in porcine NPCCs. RESULTS: The reduction in Pdx-1 gene expression caused by either Dx treatment or PGC-1α overexpression was normalized by siPGC-1α. Nuclear FOXO1 and cytoplasmic Pdx-1 were detected after Dx treatment. However, FOXO1 was observed in the cytoplasm, and Pdx-1 was observed in the nucleus after siPGC-1α. Suppression of PGC-1α by siPGC-1α improved the Dx-induced repression of insulin secretion and insulin content. In vivo studies showed that the glucose level in the Ad-siPGC-1α-infected group was significantly lower than that in the Dx-treated group. Insulin expression in the graft tissue disappeared in the Dx-injected group. However, the siPGC-1α- and Dx-treated group showed increased insulin expression and an increase in graft mass, &bgr;-cell mass, and &bgr;-cell % in the graft. Conversely, the Dx-induced ductal cystic area was markedly reduced in the siPGC-1α- and Dx-treated group. CONCLUSIONS: Our results suggest that the transdifferentiation of porcine NPCCs into &bgr; cells is influenced by the duration of the Dx treatment, which might result from the suppression of key pancreatic transcription factors. PGC-1α is an attractive target for modulating the deleterious effects of glucocorticoids on pancreatic stem cells.