Targeting PGC-1α to overcome the harmful effects of glucocorticoids in porcine neonatal pancreas cell clusters.
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 β-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, β-cell mass, and β-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 β 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.
1 Department of Endocrinology and Metabolism, The Catholic University of Korea, Seoul, Korea. 2 Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea, Seoul, Korea. 3 Address correspondence to: Kun-Ho Yoon, MD, PhD, Department of Endocrinology and Metabolism, Seoul St. Mary's Hospital, The Catholic University of Korea, #505, Banpo-Dong, Seocho-Gu 137-040, Seoul, Korea.
Ji-Won
JW
Kim
Shin-Young
SY
Park
Young-Hye
YH
You
Dong-Sik
DS
Ham
Heon-Seok
HS
Park
Seung-Hwan
SH
Lee
Hae Kyung
HK
Yang
Kun-Ho
KH
Yoon
D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000737:chemistry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D016035:Pancreas Transplantation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013234:Stem Cells / Q000166:cytology; D013552:Swine; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D003907:Dexamethasone