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Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line.
Metabolism 2006; 55(11):1464-72M

Abstract

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 alpha (TNF-alpha), 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-alpha stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-kappaB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-alpha-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-kappaB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-alpha-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-alpha 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.

Authors+Show Affiliations

Department of Diabetes and Digestive Disease, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17046548

Citation

Takeshita, Yumie, et al. "Tumor Necrosis Factor-alpha-induced Production of Plasminogen Activator Inhibitor 1 and Its Regulation By Pioglitazone and Cerivastatin in a Nonmalignant Human Hepatocyte Cell Line." Metabolism: Clinical and Experimental, vol. 55, no. 11, 2006, pp. 1464-72.
Takeshita Y, Takamura T, Hamaguchi E, et al. Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. Metab Clin Exp. 2006;55(11):1464-72.
Takeshita, Y., Takamura, T., Hamaguchi, E., Shimizu, A., Ota, T., Sakurai, M., & Kaneko, S. (2006). Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. Metabolism: Clinical and Experimental, 55(11), pp. 1464-72.
Takeshita Y, et al. Tumor Necrosis Factor-alpha-induced Production of Plasminogen Activator Inhibitor 1 and Its Regulation By Pioglitazone and Cerivastatin in a Nonmalignant Human Hepatocyte Cell Line. Metab Clin Exp. 2006;55(11):1464-72. PubMed PMID: 17046548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. AU - Takeshita,Yumie, AU - Takamura,Toshinari, AU - Hamaguchi,Erika, AU - Shimizu,Akiko, AU - Ota,Tsuguhito, AU - Sakurai,Masaru, AU - Kaneko,Shuichi, PY - 2005/12/20/received PY - 2006/06/07/accepted PY - 2006/10/19/pubmed PY - 2006/12/9/medline PY - 2006/10/19/entrez SP - 1464 EP - 72 JF - Metabolism: clinical and experimental JO - Metab. Clin. Exp. VL - 55 IS - 11 N2 - 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 alpha (TNF-alpha), 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-alpha stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-kappaB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-alpha-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-kappaB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-alpha-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-alpha 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. SN - 0026-0495 UR - https://www.unboundmedicine.com/medline/citation/17046548/Tumor_necrosis_factor_alpha_induced_production_of_plasminogen_activator_inhibitor_1_and_its_regulation_by_pioglitazone_and_cerivastatin_in_a_nonmalignant_human_hepatocyte_cell_line_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-0495(06)00222-8 DB - PRIME DP - Unbound Medicine ER -