Insulin enhanced thrombin-activable fibrinolysis inhibitor expression through PI3 kinase/Akt pathway.
Thrombin-activable fibrinolysis inhibitor (TAFI) is a key modulator of fibrinolysis. We have reported the elevated levels of plasma TAFI and their correlation with visceral fat area and insulin resistance in the patients with type 2 diabetes. Furthermore, the expression of TAFI was demonstrated in adipose tissues. Thus, we hypothesized that TAFI secreted from adipose tissues might be an important causative factor of hypofibrinolysis in patients with insulin resistance and that insulin was a modulator of the gene expression of TAFI. To evaluate this hypothesis, we examined the regulation of TAFI expression by insulin in adipocytes. TAFI mRNA was induced dose-dependently by insulin in 3T3-L1 adipocytes. PI3 kinase inhibitor wortmannin inhibited insulin-induced expression, but MEK1 inhibitor PD98059 had no effects. These data suggested that the gene expression of TAFI was regulated by PI3 kinase signaling pathway. Moreover, activated Akt induced the expression of TAFI mRNA to a similar extent by insulin in 3T3-L1 adipocytes expressing tamoxifen-regulatable Akt. In conclusion, TAFI was induced by insulin through PI3 kinase/Akt pathway in adipocytes. It is supposed that plasma TAFI levels are regulated at least in part by transcription levels in adipose tissues of patients with insulin resistance.
Hori
Yasuko
Y
Division of Diabetes and Endocrinology, Department of Internal Medicine, Mie 514-8507, Japan.
Nakatani
Kaname
K
Morioka
Kohei
K
Katsuki
Akira
A
Gabazza
Esteban C
EC
Yano
Yutaka
Y
Nobori
Tsutomu
T
Adachi
Yukihiko
Y
Sumida
Yasuhiro
Y
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D025901:Carboxypeptidase B2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic; D000077191:Wortmannin
D000730:Androstadienes; D025901:Carboxypeptidase B2; D005419:Flavonoids; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D013629:Tamoxifen; D000077191:Wortmannin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one