槲皮素通过调控内质网应激信号通路改善非酒精性脂肪肝大鼠肝脏损伤
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贵州中医药大学

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Quercetin treatment attenuates liver injury in rats with nonalcoholic fatty liver disease by modulating endoplasmic reticulum stress
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    摘要:

    目的 基于内质网应激(endoplasmic reticulum stress,ERS)信号通路探讨槲皮素对高脂饲料诱导的大鼠非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)模型的干预作用及其机制。方法 SD大鼠高脂饲料喂养8周建立NAFLD模型,之后随机分为模型组、槲皮素低剂量组(25 mg/kg)和槲皮素高剂量组(50 mg/kg),另设正常饮食大鼠作为正常对照组。各组大鼠予以相应干预,给药期间对大鼠体重、进食量进行监测。继续饲养8周后,检测大鼠血清中胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low-density lipoprotein-cholesterol,LDL-c)、高密度脂蛋白胆固醇(high-density lipoprotein-cholesterol,HDL-c)、丙氨酸氨基转移酶(glutamic-pyruvic transaminase,ALT)、天冬氨酸氨基转移酶(glutamic oxalacetic transaminase,AST)以及肝脏组织中TC、TG的含量变化;苏木素-伊红(hematoxylin-eosin,HE)染色、油红O染色、马松(Masson)染色观察大鼠肝脏组织的病理学变化;血糖仪检测大鼠血糖值并通过糖耐量实验评估大鼠糖耐量受损情况;胰岛素酶联免疫吸附试验(enzyme-linked immuno sorbent assay,ELISA)试剂盒检测各组大鼠空腹胰岛素水平;实时荧光定量PCR(Q-polymerase chain reaction,Q-PCR)法检测各组大鼠肝脏组织ERS相关基因bip、atf6、atf4、xbp-1s和chop的表达变化;蛋白质印迹(Western blot)法检测各组大鼠肝脏组织ERS相关蛋白BiP、CHOP、ATF4、ATF6、XBP-1s和XBP-1u的表达变化。结果 实验期间,各组大鼠体重、进食量无明显差异;与正常组相比较,模型组大鼠血清TG、TC、LDL-c、AST、ALT浓度增加,HDL-c浓度降低(P<0.05);与模型组相比较,槲皮素低剂量组大鼠血清TG、TC、LDL-c、AST、ALT浓度降低(P<0.05),槲皮素高剂量组大鼠血清TG、TC、AST、ALT浓度降低(P<0.05)。与正常组相比较,模型组大鼠肝脏体积增大,重量增加,肝细胞形态明显肿胀且呈空泡化,脂质沉积明显增加,且纤维化区域明显增加,同时大鼠出现胰岛素抵抗和糖耐量受损情况;与模型组相比较,以上病理改变在槲皮素低、高剂量组大鼠中有较明显改善。Q-PCR和Western blot结果显示,与正常组相比较,模型组大鼠肝脏组织中bip、atf6、atf4、xbp-1s和chop mRNA表达升高(P<0.05或P<0.01),BiP、CHOP、ATF4、ATF6和XBP-1s蛋白表达升高(P<0.05或P<0.01);与模型组相比较,槲皮素低、高剂量组大鼠肝脏组织bip、atf6、atf4、xbp-1s和chop mRNA 表达降低,BiP、CHOP、ATF4、ATF6和XBP-1s蛋白表达也有所降低(P<0.05或P<0.01)。同时,进一步体外实验证实,槲皮素可通过抑制ERS通路减轻棕榈酸诱导的肝细胞脂毒性损伤。结论 以上结果表明,槲皮素可以改善高脂饲料诱导的NAFLD大鼠脂代谢异常、糖耐量受损、肝脏脂质沉积以及病理损伤,其机制可能是通过调控ERS信号通路发挥作用。

    Abstract:

    This study aimed to investigate the potential of Quercetin (Que) in ameliorating nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD) through the modulation of endoplasmic reticulum stress (ERS) in rats. After 8 weeks of HFD feeding, rats were randomly assigned to the following groups: HFD group, HFD + low-dose Que group (25 mg?kg-1), and HFD + high-dose Que group (50 mg?kg-1). The Control group consisted of rats fed a standard chow diet. After 16 weeks, rats were euthanized, and liver tissues and blood were collected for histological, biochemical, gene, and protein expression analyses. Throughout the experiment, no significant differences in food intake and body weight were observed among the four groups.Compared to the Control group, the HFD group exhibited increased serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), glutamic oxalacetic transaminase (AST), and glutamic-pyruvic transaminase (ALT), along with decreased high-density lipoprotein-cholesterol (HDL-c) levels (P<0.05). In the low-dose Que group, serum levels of TG, TC, LDL-c, AST, and ALT were significantly reduced compared to the HFD group (P<0.05). Similarly, the high-dose Que group showed decreased serum levels of TG, TC, AST, and ALT compared to the HFD group (P<0.05). In the HFD group, the liver exhibited enlargement and increased absolute weight, with prominently swollen hepatocytes, marked vacuolization, and accumulated lipid droplets. Additionally, increased collagen deposition, insulin resistance, and impaired glucose tolerance were observed in the HFD group. However, these alterations were reversed in both low- and high-dose Que groups. Quantitative polymerase chain reaction (Q-PCR) results demonstrated that Que treatment significantly suppressed the expressions of several ERS-related genes, including bip, atf6, atf4, xbp-1s, and chop (P<0.05 or P<0.01). Furthermore, Western blot analysis revealed that Que substantially suppressed the protein expressions of ATF4, ATF6, XBP-1s, BiP, and CHOP, which were upregulated in the HFD group (P<0.05). Overall, our findings indicate that Que treatment attenuates HFD-induced aberrant lipid metabolism, impaired glucose tolerance, and hepatic lipid deposition in NAFLD rats, with modulation of the ERS-related pathway potentially playing a critical role.

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  • 收稿日期:2023-07-16
  • 最后修改日期:2023-12-03
  • 录用日期:2024-01-16
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