| RRC ID |
2062
|
| 著者 |
Goto D, Okimoto T, Ono M, Shimotsu H, Abe K, Tsujita Y, Kuwano M.
|
| タイトル |
Upregulation of low density lipoprotein receptor by gemfibrozil, a hypolipidemic agent, in human hepatoma cells through stabilization of mRNA transcripts.
|
| ジャーナル |
Arterioscler Thromb Vasc Biol
|
| Abstract |
Gemfibrozil reduces the plasmal levels of cholesterol and triglyceride in patients with hyperlipidemia by a mechanism that is not well understood. The present study evaluated the effect of gemfibrozil on the LDL receptor in human hepatoma cells compared with that of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Exposure to gemfibrozil, 40 mumol/L, for 3 days increased the binding of 125I-LDL to the surface of three lines of human hepatoma cell, HepG2, HuH7, and HLE by 1.5- to 2.0-fold. Similar findings were observed with pravastatin. Scatchard analysis with 125I-LDL indicated an increased number of LDL receptors on the cell surface of HepG2 cells when treated with gemfibrozil and pravastatin. However, the gemfibrozil-treated cells exhibited no increase in the binding of 125I-epidermal growth factor (EGF). Gemfibrozil increased the levels of LDL receptor mRNA and protein in HepG2 cells. The increase in LDL receptor activity induced by pravastatin was abolished by concomitant administration of mevalonic acid, 770 mumol/L. This effect was not seen with gemfibrozil, suggesting the mechanism differs for the two lipid-lowering drugs. To determine whether this increase in mRNA was due to transcriptional activation, we prepared HepG2 cells transfected with an LDL receptor promoter-reporter construct that contained a sterol regulatory element. The expression of LDL receptor regulated by the sterol regulatory element was increased by pravastatin, but not by gemfibrozil. We evaluated the stability of the mRNA in the presence of actinomycin D to explain the increase in the LDL receptor mRNA. Gemfibrozil prolonged the half-life of the mRNA for LDL receptor but not that for the EGF receptor. Stabilization of the LDL receptor mRNA is suggested to be the novel mode of action of gemfibrozil.
|
| 巻・号 |
17(11)
|
| ページ |
2707-12
|
| 公開日 |
1997-11-1
|
| DOI |
10.1161/01.atv.17.11.2707
|
| PMID |
9409246
|
| MeSH |
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Dactinomycin / pharmacology
ErbB Receptors / genetics
Gemfibrozil / pharmacology*
Gene Expression Regulation, Neoplastic / drug effects*
Genes, Reporter
Half-Life
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
Hypolipidemic Agents / pharmacology*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology*
Mevalonic Acid / pharmacology
Neoplasm Proteins / biosynthesis*
Neoplasm Proteins / genetics
Pravastatin / pharmacology
Promoter Regions, Genetic / genetics
RNA, Messenger / biosynthesis*
RNA, Messenger / genetics
RNA, Neoplasm / biosynthesis*
RNA, Neoplasm / genetics
Receptors, LDL / biosynthesis*
Receptors, LDL / genetics
Transfection
Tumor Cells, Cultured
Up-Regulation / drug effects*
|
| 引用数 |
15
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2(RCB0459) |
