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Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway.
Acta Pharm Sin B. 2019 Jul; 9(4):745-757.AP

Abstract

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.

Authors+Show Affiliations

Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China.Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China.Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China.Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China.Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31384535

Citation

Liu, Yayun, et al. "Silibinin Ameliorates Hepatic Lipid Accumulation and Oxidative Stress in Mice With Non-alcoholic Steatohepatitis By Regulating CFLAR-JNK Pathway." Acta Pharmaceutica Sinica. B, vol. 9, no. 4, 2019, pp. 745-757.
Liu Y, Xu W, Zhai T, et al. Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway. Acta Pharm Sin B. 2019;9(4):745-757.
Liu, Y., Xu, W., Zhai, T., You, J., & Chen, Y. (2019). Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway. Acta Pharmaceutica Sinica. B, 9(4), 745-757. https://doi.org/10.1016/j.apsb.2019.02.006
Liu Y, et al. Silibinin Ameliorates Hepatic Lipid Accumulation and Oxidative Stress in Mice With Non-alcoholic Steatohepatitis By Regulating CFLAR-JNK Pathway. Acta Pharm Sin B. 2019;9(4):745-757. PubMed PMID: 31384535.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway. AU - Liu,Yayun, AU - Xu,Wei, AU - Zhai,Ting, AU - You,Jiaojiao, AU - Chen,Yong, Y1 - 2019/02/22/ PY - 2018/10/09/received PY - 2018/12/11/revised PY - 2019/01/11/accepted PY - 2019/8/7/entrez PY - 2019/8/7/pubmed PY - 2019/8/7/medline KW - 2-NBDG, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose KW - ALT, alanine aminotransferase KW - AST, aspartate aminotransferase KW - Acox, acyl-coenzyme A oxidase X KW - Akt, serine–threonine protein kinase KW - CAT, catalase KW - CFLAR KW - CFLAR, caspase 8 and Fas-associated protein with death domain-like apoptosis regulator KW - CYP2E1, cytochrome P450 2E1 KW - CYP4A, cytochrome P450 4A KW - Cpt1α, carnitine palmitoyl transferase 1α KW - Fabp5, fatty acid-binding proteins 5 KW - GSH-Px, glutathione peroxidase KW - Gpat, glycerol-3-phosphate acyltransferase KW - HE, hematoxylin–eosin KW - HO-1, heme oxygenase 1 KW - IR, insulin resistance KW - IRS1, insulin receptor substrate 1 KW - JNK, c-Jun N-terminal kinase KW - Lipid accumulation KW - MAPK, mitogen-activated protein kinase KW - MCD, methionine- and choline-deficient KW - MCS, methionine- and choline-sufficient KW - MDA, malondialdehyde KW - MT, Masson–Trichrome KW - Mttp, microsomal triglyceride transfer protein KW - NAFLD, non-alcoholic fatty liver disease KW - NASH KW - NASH, nonalcoholic steatohepatitis KW - NF-κB, nuclear factor κB KW - NRF2, nuclear factor erythroid 2-related factor 2 KW - OA, oleic acid KW - ORO, oil red O KW - Oxidation stress KW - PA, palmitic acid KW - PI3K, phosphatidylinositol 3-hydroxy kinase KW - Pnpla3, phospholipase domain containing 3 KW - Pparα, peroxisome proliferator activated receptor α KW - SD, Sprague–Dawley KW - Scd-1, stearoyl-coenzyme A desaturase-1 KW - Silibinin KW - Srebp-1c, sterol regulatory element binding protein-1C KW - TC, total cholesterol KW - TG, triglyceride KW - pIRS1, phosphorylation of insulin receptor substrate 1 KW - pJNK, phosphorylation of c-Jun N-terminal kinase SP - 745 EP - 757 JF - Acta pharmaceutica Sinica. B JO - Acta Pharm Sin B VL - 9 IS - 4 N2 - 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. SN - 2211-3835 UR - https://www.unboundmedicine.com/medline/citation/31384535/Silibinin_ameliorates_hepatic_lipid_accumulation_and_oxidative_stress_in_mice_with_non_alcoholic_steatohepatitis_by_regulating_CFLAR_JNK_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-3835(18)31026-8 DB - PRIME DP - Unbound Medicine ER -
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