@article{oai:kanazawa-u.repo.nii.ac.jp:00013171,
 author = {Takeshita, Yumie and Takamura, Toshinari and Hamaguchi, Erika and Shimizu, Akiko and Ota, Tsuguhito and Sakurai, Masaru and Kaneko, Shuichi},
 issue = {11},
 journal = {Metabolism: Clinical and Experimental},
 month = {Nov},
 note = {Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor α (TNF-α), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-α stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-κB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-α-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-κB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-α-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-α up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production. © 2006, 金沢大学大学院医学系研究科環境社会医学},
 pages = {1464--1472},
 title = {Tumor necrosis factor-α-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line},
 volume = {55},
 year = {2006}
}