on March 24, 2005
Published online before print March 24, 2005, doi: 10.1161/01.ATV.0000163844.07815.c4
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Submitted on January 7, 2005
Accepted on February 16, 2005
Fenofibric Acid, an Active Form of Fenofibrate, Increases Apolipoprotein A-I-Mediated High-Density Lipoprotein Biogenesis by Enhancing Transcription of ATP-Binding Cassette Transporter A1 Gene in a Liver X Receptor-Dependent Manner
Reijiro Arakawa ;
From the Department of Biochemistry, Cell Biology, and Metabolism (R.A., S.Y.), Nagoya City University Graduate School of Medical Sciences, Japan; Research and Development Institute (R.A.), Grelan Pharmaceutical Co., Tokyo, Japan; Division of Biosignaling (N.T., T.N.-M.), National Institute of Health Sciences, Tokyo, Japan; and Division of Applied Life Sciences (K.U.), Graduate School of Agriculture, Kyoto University, Japan.
* To whom correspondence should be addressed. E-mail: syokoyam{at}med.nagoya-cu.ac.jp.
Objective--Fibrates are widely used drugs to reduce plasma triglyceride and increase high-density lipoprotein. Their active forms, fibric acids, are peroxisome proliferator-activated receptor-
activators, but no direct evidence has been demonstrated for their activation of ATP-binding cassette transporter A1 (ABCA1) in relation to clinically used fibrates. We investigated the reaction of fenofibric acid in this regard.
Methods and Results--Fenofibric acid was examined for the effect of increase of ABCA1 activity. It enhanced ABCA1 gene transcription and its protein level in macrophage cell line cells and fibroblasts and increased apolipoprotein A-I-mediated cellular lipid release, all in a dose-dependent manner. Enhancement of the gene transcription was examined by using a reporter assay system for LXRE and its inactive mutant. The results demonstrated that the effect of fenofibric acid is dependent on active LXRE.
Conclusions--Fenofibric acid increased transcription of ABCA1 gene in n liver X receptor-dependent manner.
Key words: fenofibrate • fibrates • PPAR
•
ABCA1 •
HDL •
cholesterol •
atherosclerosis
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