Hepatoprotective and anti-inflammatory effects of total flavonoids of Qu Zhi Ke (peel of Citrus changshan-huyou) on non-alcoholic fatty liver disease in rats via modulation of NF-κB and MAPKs
Hepatoprotective and anti-inflammatory effects of total flavonoids of Qu Zhi Ke (peel of Citrus changshan-huyou) on non-alcoholic fatty liver disease in rats via modulation of NF-κB and MAPKs
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DOI：
10.1016/j.phymed.2019.153082
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发表时间：
2019-11-01
期刊：
影响因子：
7.9
通讯作者：
Efferth, Thomas
中科院分区：
文献类型：
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作者：
Jiang Jianping;Yan Li;Efferth, Thomas
背景：柑橘类黄酮类化合物，由柚苷、柚皮苷、新橙皮苷等组成，具有治疗脂代谢紊乱的治疗活性。常山胡柚果皮（Citrus changshan-huyou，Qu Zike，QZK）是一种新的黄酮类化合物来源，但目前研究较少，假设：常山胡柚果皮中含有的黄酮类化合物可能具有抗脂代谢紊乱的作用。方法：采用高效液相色谱法测定TFCH中黄酮类化合物的化学成分，观察TFCH对大鼠非酒精性脂肪肝（NAFLD）的影响。采用高脂饲料诱导大鼠NAFLD模型，设阴性对照组、参比治疗组、模型组、TFCH低剂量组（25 mg/kg）、TFCH中剂量组（50 mg/kg）、TFCH高剂量组（100 mg/ kg）。血清和肝脏炎症细胞因子和NAFLD标志物的水平进行了生化测定。通过真实的时间PCR（qPCR）分析检测肝脏T-bet、GATA 3和TNF-α的相对mRNA表达。Western blot检测肝脏p38蛋白表达及NF-κ B B、ERK 1/2、p38磷酸化水平。生化数据显示TFCH通过抑制IL-1 β、IL-6、IL-12、TNF-α和IFN-γ显著抑制全身和肝内炎症，qPCR分析显示TFCH的抗炎机制与Th 1/Th 2相关。Western blot结果表明，TFCH通过抑制NF-κ B和MAPK的磷酸化而发挥保肝抗炎作用，其作用机制与NF-κ B和MAPK信号通路有关。结论：QZK是柑橘类黄酮的新来源，TFCH有望成为柑橘类黄酮抗NAFLD的代表。
Background: Citrus flavonoids, consisting of naringin, narirutin, neohesperidine, etc., have therapeutic activities for the treatment of lipometabolic disorders. The peel of Citrus changshan-huyou (Qu Zhi Ke, QZK) is a new source of flavonoids, but attracted little attention so far.Hypothesis: QZK should possess therapeutic effects against lipometabolic disorders due to the flavonoids it contains.Study design: In this study, we extracted and purified the flavonoids of QZK (TFCH) and established an obesity-induced non-alcoholic fatty liver disease (NAFLD) model of rats. TFCH was given orally for 8 weeks, and its anti-NAFLD effects and potential mechanism were evaluated.Methods: The flavonoid chemoprofile of TFCH was determined by using HPLC. High-fat diet was employed to induce NAFLD model in rats, and six groups were set up: negative control group, reference treatment group, model group, low-dose TFCH (25 mg/kg), intermediate-dose TFCH (50 mg/kg), and high-dose TFCH (100 mg/ kg). Serum and liver levels of inflammatory cytokines and NAFLD markers were measured biochemically. The relative mRNA expressions of liver T-bet, GATA3, and TNF-alpha were tested by real time PCR (qPCR) analysis. The protein expression of p38 and the phosphorylation of NF-kappa B, ERK1/2, and p38 in liver were tested by Western blot analysis.Results: The histopathological observation showed that TFCH attenuated hepatic lesions with significantly decreased NAFLD activity scores. The biochemical data showed that TFCH significantly suppressed both systemic and intrahepatic inflammation by inhibiting IL-1 beta, IL-6, IL-12, TNF-alpha, and IFN-gamma., and the qPCR analysis revealed a Th1/Th2 related anti-inflammatory mechanism of TFCH. Western blot results clarified that TFCH exerted hepatoprotective and anti-inflammatory effects by suppression of phosphorylated NF-kappa B and MAPKs, indicating a mechanism associated with NF-kappa B and MAPK signaling pathways.Conclusion: QZK is a new source of Citrus flavonoids for therapeutic use, and TFCH is a promising representative of Citrus flavonoids for anti-NAFLD therapy.