論文 - 詳細
| RRC ID | 67056 |
|---|---|
| 著者 | Lyu J, Imachi H, Fukunaga K, Sato S, Kobayashi T, Dong T, Saheki T, Matsumoto M, Iwama H, Zhang H, Murao K. |
| タイトル | Role of ATP-binding cassette transporter A1 in suppressing lipid accumulation by glucagon-like peptide-1 agonist in hepatocytes. |
| ジャーナル | Mol Metab |
| Abstract |
OBJECTIVE:Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) influences hepatic cholesterol transportation. Accumulation of hepatic cholesterol leads to fatty liver disease, which is improved by glucagon-like peptide 1 (GLP-1) in diabetes. Therefore, we analyzed the molecular mechanism in the regulation of hepatic ABCA1 by GLP-1 analogue exendin-4. METHODS:Hepatic ABCA1 expression and transcription were checked by western blotting, real-time polymerase chain reaction (PCR), and luciferase assay in HepG2 cells. Chromatin immunoprecipitation (ChIP) and site-directed mutagenesis were employed to determine transcriptional regulation of the ABCA1 gene. Prolactin regulatory element-binding (PREB)-transgenic mice were generated to access the effect of exendin-4 on improving lipid accumulation caused by a high-fat diet (HFD). RESULTS:Exendin-4 stimulated hepatic ABCA1 expression and transcription via the Ca2+/calmodulin (CaM)-dependent protein kinase kinase/CaM-dependent protein kinase IV (CaMKK/CaMKIV) pathway, whereas GLP-1 receptor antagonist exendin9-39 cancelled this effect. Therefore, exendin-4 decreased hepatic lipid content. ChIP showed that PREB could directly bind to the ABCA1 promoter, which was enhanced by exendin-4. Moreover, PREB stimulated ABCA1 promoter activity, and mutation of PREB-binding site in ABCA1 promoter cancelled exendin-4-enhanced ABCA1 promoter activity. Silencing of PREB attenuated the effect of exendin-4 and induced hepatic cholesterol accumulation. Blockade of CaMKK by STO-609 or siRNA cancelled the upregulation of ABCA1 and PREB induced by exendin-4. In vivo, exendin-4 or overexpression of PREB increased hepatic ABCA1 expression and decreased hepatic lipid accumulation and high plasma cholesterol caused by a HFD. CONCLUSIONS:Our data shows that exendin-4 stimulates hepatic ABCA1 expression and decreases lipid accumulation by the CaMKK/CaMKIV/PREB pathway, suggesting that ABCA1 and PREB might be the therapeutic targets in fatty liver disease. |
| 巻・号 | 34 |
| ページ | 16-26 |
| 公開日 | 2020-4-1 |
| DOI | 10.1016/j.molmet.2019.12.015 |
| PII | S2212-8778(20)30001-6 |
| PMID | 32180556 |
| PMC | PMC6997505 |
| MeSH | ATP Binding Cassette Transporter 1 / genetics ATP Binding Cassette Transporter 1 / metabolism* Animals Exenatide / pharmacology Glucagon-Like Peptide 1 / agonists* Glucagon-Like Peptide 1 / metabolism Hep G2 Cells Hepatocytes / drug effects* Hepatocytes / metabolism* Humans Lipid Metabolism / drug effects Mice Mice, Transgenic Tumor Cells, Cultured |
| IF | 6.448 |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2 |