关键词： 2-NBDG, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose ALT, alanine aminotransferase AST, aspartate aminotransferase Acox, acyl-coenzyme A oxidase X Akt, serine–threonine protein kinase CAT, catalase CFLAR CFLAR, caspase 8 and Fas-associated protein with death domain-like apoptosis regulator CYP2E1, cytochrome P450 2E1 CYP4A, cytochrome P450 4A Cpt1α, carnitine palmitoyl transferase 1α Fabp5, fatty acid-binding proteins 5 GSH-Px, glutathione peroxidase Gpat, glycerol-3-phosphate acyltransferase HE, hematoxylin–eosin HO-1, heme oxygenase 1 IR, insulin resistance IRS1, insulin receptor substrate 1 JNK, c-Jun N-terminal kinase Lipid accumulation MAPK, mitogen-activated protein kinase MCD, methionine- and choline-deficient MCS, methionine- and choline-sufficient MDA, malondialdehyde MT, Masson–Trichrome Mttp, microsomal triglyceride transfer protein NAFLD, non-alcoholic fatty liver disease NASH NASH, nonalcoholic steatohepatitis NF-κB, nuclear factor κB NRF2, nuclear factor erythroid 2-related factor 2 OA, oleic acid ORO, oil red O Oxidation stress PA, palmitic acid PI3K, phosphatidylinositol 3-hydroxy kinase Pnpla3, phospholipase domain containing 3 Pparα, peroxisome proliferator activated receptor α SD, Sprague–Dawley Scd-1, stearoyl-coenzyme A desaturase-1 Silibinin Srebp-1c, sterol regulatory element binding protein-1C TC, total cholesterol TG, triglyceride pIRS1, phosphorylation of insulin receptor substrate 1 pJNK, phosphorylation of c-Jun N-terminal kinase

来  源：   DOI：10.1016/j.apsb.2019.02.006   PDF(Sci-hub)   PDF(Pubmed)

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.
摘要：
非酒精性脂肪性肝炎（NASH）是一种慢性代谢综合征，CFLAR-JNK通路可以逆转NASH的过程。虽然水飞蓟宾在临床上用于治疗NASH，其对NASH中CFLAR-JNK通路的影响尚不清楚。本研究旨在研究水飞蓟宾在体内和体外NASH模型中对CFLAR-JNK通路的影响。使用饲喂甲硫氨酸-胆碱缺乏饮食并同时用水飞蓟宾处理6周的雄性C57BL/6小鼠进行体内研究。体外研究是通过使用小鼠NCTC-1469细胞进行的，分别用油酸和棕榈酸预处理，和腺病毒向下Cflar持续24小时，然后用水飞蓟宾治疗24小时。药物治疗后，CFLAR-JNK通路涉及的关键指标包括肝损伤，确定脂质代谢和氧化应激。水飞蓟宾显著激活CFLAR并抑制JNK的磷酸化,上调Pparα的mRNA表达，Fabp5,Cpt1α,Acox,Scd-1,Gpat和Mttp,降低血清ALT和AST的活性和肝脏TG的含量，TC和MDA，增加NRF2的表达和CAT的活性，GSH-Px和HO-1，并降低体内CYP2E1和CYP4A的活性和表达。这些作用通过体外实验得到证实。水飞蓟宾通过调节CFLAR-JNK通路预防NASH，从而一方面促进肝脏中脂肪酸的β-氧化和外排以减轻脂质积累，另一方面诱导抗氧化酶活性(CAT，GSH-Px和HO-1）并抑制前氧化酶活性（CYP2E1和CYP4A）以缓解氧化应激。
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