Title
Studies on the mechanism of fibrate-inhibited expression of plasminogen activator inhibitor-1 in cultured hepatocytes from cynomolgus monkey
Author
Arts, J.
Kooistra, T.
Gaubius Laboratory TNO Preventie en Gezondheid
Publication year
1997
Abstract
Fibrates are widely used drugs in hyperlipidemic disorders. In addition to lowering serum triglyceride levels, fibrates have also been shown to reduce elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels in vivo. We demonstrate that fibrates suppress PAI-1 synthesis in cultured cynomolgus monkey hepatocytes in a concentration dependent way (0.1 to 1.0 mmol/L) and independent of their lipid-lowering effect. Different fibrates showed different potency in suppressing PAI-1 production: gemfibrozil and clofibric acid, at a concentration of 1 mmol/L, reduced PAI-1 synthesis over 24 hours to 52±20% and 60±5%, while clofibrate and bezafibrate lowered PAI- 1 synthesis to only 86±17% and 84±15% of control values, respectively. These changes in PAI-1 production by fibrates correlated with changes in PAI- 1 mRNA levels and were also visible at the level of gene transcription. Fibrates did not lower basal PAI-1 synthesis but attenuated an acceleration of PAI-1 production during culture. The suppressing effect of fibrates on PAI-1 synthesis could not be mimicked with activators or inhibitors of protein kinase C (PKC). Furthermore, fibrates did not inhibit the increase in PAI-1 synthesis induced by epidermal growth factor or transforming growth factor-β. These results make mechanisms involving PKC modulation or growth factor receptor inactivation as a mode of action of fibrates unlikely. The suppressing effect of fibrates on PAI-1 synthesis could involve the nuclear receptor peroxisome proliferator-activated receptor (PPAR) and its heterodimeric partner, the retinoid X receptor (RXR). The alpha forms of PPAR and RXR were both found to be expressed in cynomolgus monkey hepatocytes. The ligand for RXRα, 9-cis retinoic acid, suppressed PAI-1 synthesis to the same extent as gemfibrozil, while a combination of gemfibrozil and 9-cis retinoic acid had no more effect on PAI-1 synthesis than any of these compounds alone at optimal concentrations. In conclusion, fibrates downregulate an induced PAI-1 production in cynomolgus monkey hepatocytes independent of a decrease in triglyceride levels. A possible involvement of PPARα/RXRα in this downregulation is discussed.
Subject
Biology
9-cis retinoic acid
fibrates
hepatocytes
peroxisome proliferator-activated receptor
plasminogen activator inhibitor-1
2 [1 (3 amidinothiopropyl) 1h indol 3 yl] 3 (1 methyl 1h indol 3 yl)maleimide
alitretinoin
antilipemic agent
epidermal growth factor
fibric acid derivative
gemfibrozil
peroxisome proliferator
phorbol 13 acetate 12 myristate
plasminogen activator inhibitor 1
protein kinase C
protein kinase C inhibitor
retinoid X receptor
transforming growth factor beta
animal cell
controlled study
dose time effect relation
drug mechanism
enzyme activity
gene expression
hyperlipidemia
liver cell culture
monkey
nonhuman
Animals
Antilipemic Agents
Cells, Cultured
Dose-Response Relationship, Drug
Liver
Macaca fascicularis
Plasminogen Activator Inhibitor 1
RNA, Messenger
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TNO identifier
233811
ISSN
1079-5642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 17 (1), 26-32
Document type
article