Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway
| Autor: | Wei Xu, You Jiaojiao, Yong Chen, Yayun Liu, Ting Zhai |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Lipid accumulation
AST aspartate aminotransferase HO-1 heme oxygenase 1 Pharmacology Gpat glycerol-3-phosphate acyltransferase medicine.disease_cause PI3K phosphatidylinositol 3-hydroxy kinase chemistry.chemical_compound pIRS1 phosphorylation of insulin receptor substrate 1 0302 clinical medicine IR insulin resistance Pnpla3 phospholipase domain containing 3 Mttp microsomal triglyceride transfer protein General Pharmacology Toxicology and Pharmaceutics 0303 health sciences TG triglyceride NASH CYP2E1 cytochrome P450 2E1 HE hematoxylin–eosin CYP2E1 Fabp5 fatty acid-binding proteins 5 pJNK phosphorylation of c-Jun N-terminal kinase 030220 oncology & carcinogenesis JNK c-Jun N-terminal kinase NRF2 nuclear factor erythroid 2-related factor 2 IRS1 insulin receptor substrate 1 NF-κB nuclear factor κB Pparα peroxisome proliferator activated receptor α NASH nonalcoholic steatohepatitis Original article NAFLD non-alcoholic fatty liver disease GSH-Px glutathione peroxidase MT Masson–Trichrome CFLAR caspase 8 and Fas-associated protein with death domain-like apoptosis regulator MCS methionine- and choline-sufficient Silibinin Cpt1α carnitine palmitoyl transferase 1α CFLAR PA palmitic acid 03 medical and health sciences In vivo ALT alanine aminotransferase CYP4A cytochrome P450 4A medicine Srebp-1c sterol regulatory element binding protein-1C Acox acyl-coenzyme A oxidase X Oxidation stress 030304 developmental biology MCD methionine- and choline-deficient MDA malondialdehyde Methionine lcsh:RM1-950 OA oleic acid 2-NBDG 2-(N-(7-nitrobenz-2-oxa-1 3-diazol-4-yl) amino)-2-deoxyglucose Lipid metabolism Scd-1 stearoyl-coenzyme A desaturase-1 medicine.disease TC total cholesterol lcsh:Therapeutics. Pharmacology chemistry ORO oil red O SD Sprague–Dawley CAT catalase Steatohepatitis Akt serine–threonine protein kinase MAPK mitogen-activated protein kinase Oxidative stress |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 9, Iss 4, Pp 745-757 (2019) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| DOI: | 10.1016/j.apsb.2019.02.006 |
| Popis: | Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A in vivo. These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress. Graphical abstract Silibinin could regulate CFLAR-JNK pathway to ameliorates hepatic lipid accumulation, insulin resistence and oxidative stress in C57BL/6 mice treated by methionine- and choline-deficient diet, and NCTC-1469 cells treated by the mixture of oleic acid and palmitic acid and adenovirus-down Cflar.fx1 |
| Databáze: | OpenAIRE |
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