論文 - 詳細
| RRC ID | 41928 |
|---|---|
| 著者 | Morishima A, Ohkubo N, Maeda N, Miki T, Mitsuda N. |
| タイトル | NFkappaB regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor alpha. |
| ジャーナル | J Biol Chem |
| Abstract |
The levels of plasma HDL cholesterol and apoA-I in NFkappaB p50 subunit-deficient mice were significantly higher than those in wild-type mice under regular and high fat diets, without any significant difference in the level of total cholesterol. To examine the role of NFkappaBin lipid metabolism, we studied its effect on the regulation of apoA-I secretion from human hepatoma HepG2 cells. Lipopolysaccharide-induced activation of NFkappaB reduced the expression of apoA-I mRNA and protein, whereas adenovirus-mediated expression of IkappaBalpha super-repressor ameliorated the reduction. This IkappaBalpha-induced apoA-I increase was blocked by preincubation with MK886, a selective inhibitor of peroxisome proliferator-activated receptor alpha (PPARalpha), suggesting that NFkappaB inactivation induces apoA-I through activation of PPARalpha. To further support this idea, the expression of IkappaBalpha increased apoA-I promoter activity, and this increase was blocked by preincubation with MK886. Mutations in the putative PPARalpha-binding site in the apoA-I promoter or lack of the site abrogated these changes. Taking these results together, inhibition of NFkappaB increases apoA-I and HDL cholesterol through activation of PPARalpha in vivo and in vitro. Our data suggest a new aspect of lipid metabolism and may lead to a new paradigm for prevention and treatment of atherosclerotic disease. |
| 巻・号 | 278(40) |
| ページ | 38188-93 |
| 公開日 | 2003-10-3 |
| DOI | 10.1074/jbc.M306336200 |
| PII | S0021-9258(20)83118-4 |
| PMID | 12882972 |
| MeSH | Adenoviridae / genetics Adenoviridae / metabolism Animals Apolipoprotein A-I / genetics Apolipoprotein A-I / metabolism* Apolipoproteins / metabolism Apolipoproteins B / metabolism Apolipoproteins E / metabolism Arteriosclerosis / metabolism Binding Sites Cholesterol / metabolism Cholesterol, HDL / metabolism* Electrophoresis, Polyacrylamide Gel Female Gene Expression Regulation* Genes, Reporter Genotype Humans Immunoblotting Indoles / pharmacology Lipid Metabolism Lipopolysaccharides / metabolism Lipoproteins / chemistry Lipoxygenase Inhibitors / pharmacology Mice Mice, Inbred C57BL Models, Genetic Mutation NF-kappa B / metabolism* NF-kappa B / physiology* Plasmids / metabolism Promoter Regions, Genetic RNA, Messenger / metabolism Receptors, Cytoplasmic and Nuclear / metabolism* Reverse Transcriptase Polymerase Chain Reaction Transcription Factors / metabolism* Transcriptional Activation Transfection Tumor Cells, Cultured |
| IF | 4.238 |
| 引用数 | 56 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2 |