PPAR alpha activation protects against cholestatic liver injury
Zhao, Qi1,2; Yang, Rui1,2; Wang, Jing1; Hu, Dan-Dan1,3,4; Li, Fei1
AbstractIntrahepatic 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.
KeywordPrimary Biliary-cirrhosis Bile-acid Homeostasis Receptor-alpha Ursodeoxycholic Acid Cholesterol 7-alpha-hydroxylase Beta-oxidation Fenofibrate Therapy Mice Hepatotoxicity
Subject AreaMultidisciplinary Sciences
Indexed BySCI
WOS IDWOS:000408622400061
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Cited Times:52[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Affiliation1.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
Recommended Citation
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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