地菍总黄酮改善大鼠非酒精性脂肪肝的作用机制

doi:10.16431/j.cnki.1671-7236.2025.08.042

摘要/Abstract

摘要： 【目的】探讨地菍总黄酮(total flavonoids of Melastoma dodecandrum Lour.，TFMD)对大鼠非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)的影响及作用机制。【方法】体外试验将HepG2细胞分为6组，空白对照组、NAFLD模型组、TFMD高、中、低剂量组(25、50、100 μg/mL TFMD)及铁死亡抑制剂组(2 μmol/L Fer-1)，每组6个复孔。除空白对照组外，其余各组均采用0.25 mmol/L棕榈酸处理HepG2细胞24 h建立细胞模型，TFMD低、中、高剂量组和铁死亡抑制剂组HepG2细胞分别用相应浓度的TFMD和Fer-1处理24 h。细胞毒性试验测定细胞活力；利用相关试剂盒检测HepG2细胞内总胆固醇(TC)和甘油三酯(TG)含量；通过检测超氧化物歧化酶(SOD)活性、谷胱甘肽(GSH)和丙二醛(MDA)含量，评估TFMD对NAFLD体外模型脂质过氧化水平的影响；通过DCFH-DA荧光探针法检测HepG2细胞活性氧(ROS)水平。体内试验采用高脂肪饲料喂养SD大鼠，建立NAFLD大鼠模型，将大鼠随机分为6组：空白对照组、NAFLD模型组、TMFD高、中、低剂量组、多烯磷脂酰胆碱(PPC)组，每组10只。判定造模成功后即给予相应药物干预，PPC组灌胃给予PPC(0.07 g/kg BW)，TMFD低、中、高剂量组分别灌胃给予TMFD(0.33、0.50和0.75 g/kg BW)，共干预6周，空白对照组和NAFLD模型组给予等体积生理盐水。治疗期结束后，利用相关试剂盒检测NAFLD大鼠血清中的TG、TC、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)含量、谷丙转氨酶(ALT)、谷草转氨酶(AST)活性及NAFLD大鼠肝脏中MDA、Fe²⁺含量、总抗氧化能力(T-AOC)、过氧化氢酶(CAT)活性；利用HE和油红O分别染色观察NAFLD大鼠肝脏病理变化，运用Western blotting检测各组大鼠肝脏组织中核转录因子E2相关因子2(Nrf2)、过氧化物酶体增殖物激活受体γ(PPARγ)、过氧化物酶体增殖受体γ辅激活因子1α(PGC-1α)、NAD(P)H醌脱氢酶1 (NQO1)、RelA(NF-κB P65)、谷胱甘肽过氧化物酶4(GPX4)、Kelch样ECH相关蛋白1(Keap1)蛋白表达。【结果】体外试验结果显示，与空白对照组相比，NAFLD模型组HepG2细胞活力极显著降低(P＜0.01)，TG、TC和MDA含量极显著升高(P＜0.01)，GSH含量及SOD活性极显著降低(P＜0.01)，ROS 水平极显著上升(P＜0.01),荧光强度明显增强。与NAFLD模型组相比，TFMD各剂量组及Fer-1组HepG2细胞活力极显著升高(P＜0.01)；TG、TC和MDA含量极显著降低(P＜0.01)，GSH含量及SOD活性极显著升高(P＜0.01)，ROS水平极显著下降(P＜0.01),荧光强度明显降低。体内试验结果显示，与空白对照组相比，NAFLD模型组大鼠血清中HDL-C含量极显著降低(P＜0.01)，TC、TG、LDL-C含量极显著升高(P＜0.01)；与NAFLD模型组相比，TMFD各剂量组及PPC组大鼠血清中HDL-C含量极显著或显著上升(P＜0.01；P＜0.05)，LDL-C含量极显著或显著降低(P＜0.01；P＜0.05)，TG和TC含量极显著降低(P＜0.01)。病理学观察结果显示，与空白对照组相比，NAFLD模型组大鼠肝细胞出现大量的脂肪空泡，排列错乱不均，肝细胞内脂肪变性程度严重，肝细胞中出现大量的红色脂滴，脂滴体积变大并有一定的聚集趋势。TMFD各剂量组和PPC组肝细胞形态齐整，脂肪变性程度显著下降，肝脏中红色脂滴的数量减少，体积变小。与空白对照组相比，NAFLD模型组大鼠血清中AST和ALT活性极显著升高(P＜0.01)，肝脏中CAT活性和T-AOC极显著下降(P＜0.01)，MDA和Fe²⁺含量极显著升高(P＜0.01)；与NAFLD模型组相比，TFMD各剂量组和PPC组大鼠血清中AST和ALT活性极显著或显著降低(P＜0.01；P＜0.05)，TFMD各剂量组及PPC组大鼠肝脏中MDA含量极显著或显著降低(P＜0.01；P＜0.05)，T-AOC极显著或显著上升(P＜0.01；P＜0.05)，CAT活力极显著升高(P＜0.01)，Fe²⁺含量极显著下降(P＜0.01)。Western blotting结果表明，与空白对照组相比，NAFLD模型组大鼠肝脏中PPARγ、PGC-1α、Nrf2、NQO1和GPX4蛋白表达量极显著降低(P＜0.01)，Keap1和NF-κB P65蛋白表达量极显著升高(P＜0.01)；与NAFLD模型组相比，TFMD各剂量组和PPC组大鼠肝脏中PPARγ、PGC-1α、Nrf2、NQO1和GPX4蛋白表达量极显著升高(P＜0.01)，Keap1和NF-κB P65蛋白表达量极显著降低(P＜0.01)。【结论】 TFMD对NAFLD的干预作用机制与调节机体脂质过氧化失衡、铁代谢紊乱，进而抑制肝脏中相关细胞发生铁死亡相关，TFMD通过调节PPARγ/PGC-1α/Nrf2信号通路，延缓NAFLD疾病进程。

关键词: 地菍总黄酮; 非酒精性脂肪肝; 铁死亡; PPARγ/PGC-1α/Nrf2通路; 作用机制

Abstract: 【Objective】 The purpose of this study was to investigate the effect and mechanism of total flavonoids of Melastoma dodecandrum Lour.(TFMD) on nonalcoholic fatty liver disease (NAFLD) in rats. 【Method】 In vitro,HepG2 cells were divided into 6 groups:Control group,NAFLD model group,TFMD high,medium and low dose groups (25,50 and 100 μg/mL TFMD),iron death inhibitor group (Fer-1,2 μmol/L Fer-1),6 duplicate wells per group.HepG2 cells were treated with 0.25 mmol/L palmitic acid for 24 h to establish cell model in all groups except for control group,and HepG2 cells in TFMD low,medium and high dose groups and the iron death inhibitor group were treated with corresponding concentrations of TFMD and Fer-1 for 24 h,respectively.The cell viability was determined by cytotoxicity assay.The contents of total cholesterol (TC) and triglyceride (TG) in HepG2 cells were detected by related kits,and the effects of TFMD on the lipid peroxidation level of NAFLD in vitro model were evaluated by detecting the activities of superoxide dismutase (SOD),contents of glutathione (GSH) and malondialdehyde (MAD).The level of reactive oxygen species (ROS) in HepG2 cells was detected by DCFH-DA fluorescence probe method.In vivo,SD rats were fed with high fat diet to establish NAFLD model,and were randomly divided into 6 groups:Control group,NAFLD model group,TMFD high,middle and low dose groups,and polyene phosphatidylcholine (PPC) group,with 10 rats in each group.After the success of modeling was judged,the corresponding drug intervention was given immediately.Rats in PPC group were given intragastric administration of PPC (0.07 g/kg BW),and the rats in TMFD low,medium and high dose groups were given intragastric administration of TMFD (0.33,0.50 and 0.75 g/kg BW) for 6 weeks.Rats in control group and NAFLD model group were given the same volume of saline.At the end of the treatment period,the contents of TG,TC,high density lipoprotein cholesterol (HDL-C),low density lipoprotein cholesterol (LDL-C),the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of NAFLD rats, the contents of MDA and Fe²⁺,and the total antioxidant capacity (T-AOC) and the activity of catalase (CAT) in liver of NAFLD rats were detected by related kits.The hepatic pathological changes of NAFLD rats were observed by hematoxylin-eosin staining and oil red O staining.The expression of NF-E2-related factor 2 (Nrf2),peroxisome proliferator-activated receptor γ (PPARγ),peroxisome proliferative receptor gamma coactivator 1α (PGC-1α),NAD(P)H quinone dehydrogenase 1 (NQO1),RelA (NF-κB P65),glutathione peroxidase 4 (GPX4) and Kelch-like ECH-associated protein 1 (Keap1) were detected by Western blotting. 【Result】 In vitro test results showed that compared with control group,the activity of HepG2 cells in NAFLD model group was extremely significantly decreased (P＜0.01),the contents of TG,TC and MDA were extremely significantly increased (P＜0.01),and the content of GSH and activity of SOD were extremely significantly decreased (P＜0.01).The level of ROS in HepG2 cells was extremely significantly increased (P＜0.01),and the fluorescence intensity was significantly enhanced.Compared with NAFLD model group,the activity of HepG2 cells in TFMD groups and Fer-1 group was extremely significantly increased (P＜0.01),the contents of TG,TC and MDA were extremely significantly decreased (P＜0.01),and the content of GSH and activity of SOD were extremely significantly increased (P＜0.01).The level of ROS in HepG2 cells was extremely significantly decreased (P＜0.01),and the fluorescence intensity was significantly decreased.The results of in vivo study showed that compared with control group,the content of HDL-C in serum of rats in NAFLD model group was extremely significantly decreased (P＜0.01),while the contents of TC,TG and LDL-C were extremely significantly increased (P＜0.01).Compared with NAFLD model group,the content of HDL-C in serum of rats in TFMD groups and PPC group was extremely significantly or significantly increased (P＜0.01 or P＜0.05),the content of LDL-C was extremely significantly or significantly decreased (P＜0.01 or P＜0.05),and the contents of TG and TC were extremely significantly decreased (P＜0.01).Pathological observation showed that compared with control group,the hepatocytes of the NAFLD model group had a large number of fat vacuoles,disorderly and uneven arrangement,severe fatty degeneration in the hepatocytes,a large number of red lipid droplets in the hepatocyte,and the volume of lipid droplets became larger and had a certain tendency to aggregate.The morphology of hepatocytes was neat,the degree of fatty degeneration was significantly decreased,the number of red lipid droplets in the liver was reduced,and the volume became smaller in TMFD groups and PPC group.Compared with control group,the activities of AST and ALT in serum of rats in NAFLD model group were extremely significantly increased (P＜0.01),the activity of CAT and T-AOC in the liver of rats in NAFLD model group were extremely significantly decreased (P＜0.01),and the contents of MDA and Fe²⁺ were extremely significantly increased (P＜0.01).Compared with NAFLD model group,the activities of AST and ALT in serum of rats in TFMD groups and PPC group were extremely significantly or significantly decreased (P＜0.01 or P＜0.05),the content of MDA in liver of rats in TFMD groups and PPC group was extremely significantly or significantly decreased (P＜0.01 or P＜0.05), T-AOC was extremely significantly or significantly increased (P＜0.01 or P＜0.05),the activity of CAT was extremely significantly increased (P＜0.01),and the content of Fe²⁺ was extremely significantly decreased (P＜0.01).Western blotting results showed that the expressions of PPARγ,PGC-1α,Nrf2,NQO1 and GPX4 proteins in liver of rats in NAFLD model group were extremely significantly lower than those in control group (P＜0.01),the expressions of Keap1 and NF-κB P65 proteins were extremely significantly increased (P＜0.01).Compared with NAFLD model group,the expressions of PPARγ,PGC-1α,Nrf2,NQO1 and GPX4 proteins were extremely significantly increased (P＜0.01) in TFMD groups and PPC group,the expressions of Keap1 and NF-κB P65 proteins were extremely significantly decreased (P＜0.01). 【Conclusion】 The mechanism of TFMD intervention on NAFLD was related to the regulation of iron metabolism and lipid peroxidation imbalance in the body,and TFMD inhibit the iron death of related cells in the liver by regulating PPARγ/PGC-1α/Nrf2 signaling pathway.

Key words: total flavonoids of Melastoma dodecandrum Lour.; NAFLD; ferroptosis; PPARγ/PGC-1α/Nrf2 pathway; mechanism of action

中图分类号:

S853.74

李笑笑, 杨秋莉, 柯金城, 林惠旅, 刘呈香, 杨媛媛, 农丕豪, 蒋寒婷, 李丽. 地菍总黄酮改善大鼠非酒精性脂肪肝的作用机制[J]. 中国畜牧兽医, 2025, 52(8): 3939-3953.

LI Xiaoxiao, YANG Qiuli, KE Jincheng, LIN Huilyu, LIU Chengxiang, YANG Yuanyuan, NONG Pihao, JIANG Hanting, LI Li. Mechanism of Action of Total Flavonoids of Melastoma dodecandrum Lour.Improving Nonalcoholic Fatty Liver Disease in Rats[J]. China Animal Husbandry & Veterinary Medicine, 2025, 52(8): 3939-3953.

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