| PPAR alpha activation protects against cholestatic liver injury | |
Zhao, Qi1,2 ; Yang, Rui1,2; Wang, Jing1; Hu, Dan-Dan1,3,4; Li, Fei1
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| 2017-08-30 | |
| 发表期刊 | SCIENTIFIC REPORTS
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| ISSN | 2045-2322 |
| 卷号 | 7页码:9967 |
| 摘要 | Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which ultimately may lead to liver fibrosis and cirrhosis. Here, the preventive and therapeutic effects of peroxisome proliferator-activated receptor alpha (PPAR alpha) signaling activated by fenofibrate was evaluated on cholestatic liver damage. Metabolomic analysis revealed that alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis resulted in the accumulation of serum long-chain acylcarnitines and triglyceride, and the reduced expression of four fatty acid beta-oxidation (beta-FAO) relevant genes (Cpt1b, Cpt2, Mcad and Hadha), indicating the disruption of beta-FAO. The increase of acylcarnitines in hepatic cell resulted in the enhanced expression of anti-oxidative genes glutathione S-transferases (Gsta2 and Gstm3) directly. As direct PPAR alpha-regulated genes, Cpt1b, Cpt2, and Mcad were up-regulated after pretreatment with PPAR alpha agonist, fenofibrate, indicating the improvement of beta-FAO. In the end, the disrupted bile acid metabolism in the enterohepatic circulation and the enhanced oxidative stress and inflammation cytokines induced by ANIT exposure were significantly recovered with the improvement of beta-FAO using fenofibrate treatment. These findings provide the rationale for the use of PPAR alpha agonists as therapeutic alternatives for cholestatic liver damage. |
| 关键词 | Primary Biliary-cirrhosis Bile-acid Homeostasis Receptor-alpha Ursodeoxycholic Acid Cholesterol 7-alpha-hydroxylase Beta-oxidation Fenofibrate Therapy Mice Hepatotoxicity |
| 学科领域 | Multidisciplinary Sciences |
| DOI | 10.1038/s41598-017-10524-6 |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000408622400061 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://ir.kib.ac.cn/handle/151853/54911 |
| 专题 | 中国科学院东亚植物多样性与生物地理学重点实验室 |
| 作者单位 | 1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Kunming Med Univ, Sch Pharmaceut Sci, Kunming 650500, Yunnan, Peoples R China 4.Kunming Med Univ, Yunnan Key Lab Pharmacol Nat Prod, Kunming 650500, Yunnan, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Qi,Yang, Rui,Wang, Jing,et al. PPAR alpha activation protects against cholestatic liver injury[J]. SCIENTIFIC REPORTS,2017,7:9967. |
| APA | Zhao, Qi,Yang, Rui,Wang, Jing,Hu, Dan-Dan,&Li, Fei.(2017).PPAR alpha activation protects against cholestatic liver injury.SCIENTIFIC REPORTS,7,9967. |
| MLA | Zhao, Qi,et al."PPAR alpha activation protects against cholestatic liver injury".SCIENTIFIC REPORTS 7(2017):9967. |
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