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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 40507042 Takeshita, Yumie 00324111 Takamura, Toshinari 10436818 Hamaguchi, Erika Shimizu, Akiko 60397213 Ota, Tsuguhito Sakurai, Masaru 60185923 Kaneko, Shuichi 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 Elsevier BV 2006-11-01 2017-10-03 eng journal article AM http://hdl.handle.net/2297/2870 https://kanazawa-u.repo.nii.ac.jp/records/13171 https://doi.org/10.1016/j.metabol.2006.06.016 http://www.elsevier.com/locate/issn/00260495 0026-0495 Metabolism: Clinical and Experimental 55 11 1464 1472 https://kanazawa-u.repo.nii.ac.jp/record/13171/files/ME-PR-TAKAMURA-T-05.pdf application/pdf 253.8 kB 2017-10-03