Suppression of peroxisome proliferator-activated receptor gamma-coactivator-1alpha normalizes the glucolipotoxicity-induced decreased BETA2/NeuroD gene transcription and improved glucose tolerance in diabetic rats.
Peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1alpha expression protects against beta-cell dysfunction in vivo and determined the mechanism of action of PGC-1alpha in beta-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1alpha in glucolipotoxicity-associated beta-cell dysfunction. The expression of PGC-1alpha in cultured beta-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1alpha also suppressed the expression of the insulin and beta-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1alpha small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1alpha but were rescued by Ad-siPGC-1alpha. PGC-1alpha binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1alpha. Ad-siPGC-1alpha injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1alpha expression protects the glucolipotoxicity-induced beta-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1alpha, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.
Kim
Ji-Won
JW
Department of Internal Medicine, The Catholic University of Korea, Kangnam St Mary's Hospital, Seoul 137-040, Korea.
You
Young-Hye
YH
Ham
Dong-Sik
DS
Cho
Jae-Hyoung
JH
Ko
Seung-Hyun
SH
Song
Ki-Ho
KH
Son
Ho-Young
HY
Suh-Kim
Haeyoung
H
Lee
In-Kyu
IK
Yoon
Kun-Ho
KH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D010180:Pancreatectomy; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D051792:Basic Helix-Loop-Helix Proteins; D005227:Fatty Acids; D005947:Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C490555:Neurod1 protein, rat; C501429:Ppargc1a protein, rat