Activation of PPARgamma negatively regulates O-GlcNAcylation of Sp1.
O-GlcNAcylation is a kind of post-translational modification and many nuclear and cytoplasmic proteins are O-GlcNAcylated. In this study, we demonstrated that thiazolidinediones (TZDs), which are used as insulin sensitizer, specifically inhibited the O-GlcNAcylation of Sp1 but did not affect the O-GlcNAcylation of the total proteins in cell culture systems and mouse models. This effect was mediated by peroxisome proliferator activated receptor gamma (PPARgamma) activation and probably by synthesis of a specific protein induced by PPARgamma activation. In addition, we demonstrated that the O-GlcNAcylation sites in the zinc-finger domain were involved in the transcriptional activation of Sp1 and that rosiglitazone, a member of TZDs, affected Sp1 transcriptional activity partially by regulating the O-GlcNAcylation level of these sites. Considering the role of hexosamine biosynthesis pathway in hyperglycemia-induced insulin resistance and Sp1 in the hyperglycemia-induced gene expression, the regulation of Sp1 O-GlcNAcylation by TZDs may help to explain the function of TZDs as a treatment for insulin resistance and diabetes.
Chung
Sung Soo
SS
Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea.
Kim
Ji Hyun
JH
Park
Ho Seon
HS
Choi
Hye Hun
HH
Lee
Kyeong Won
KW
Cho
Young Min
YM
Lee
Hong Kyu
HK
Park
Kyong Soo
KS
D000117:Acetylglucosamine / Q000096:biosynthesis / Q000378:metabolism*; D000215:Acylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D000077154:Rosiglitazone; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic; D016335:Zinc Fingers
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000117:Acetylglucosamine