目的 基于代謝組學(xué)方法探討黃芪赤風(fēng)湯（ HQCF）對頸動脈粥樣硬化（ CAS）大鼠的肝臟脂質(zhì)代謝的作用機(jī)制。方法 SD大鼠隨機(jī)分為5組：假手術(shù)組、模型組、阿托伐他汀鈣片（ Ato，1.8 mg·kg^-1）組和HQCF低、高劑量（1.53、3.06 g·kg^-1）組，采用動脈鉗夾術(shù)聯(lián)合高脂飼料喂養(yǎng)建立大鼠CAS模型，假手術(shù)組大鼠只做分離頸動脈處理而不使用血管鉗，喂食基礎(chǔ)飼料。造模時間持續(xù)12周，造模結(jié)束后ig給藥，每天1次，持續(xù)28 d。HE染色評估大鼠頸動脈、肝臟的病理學(xué)形態(tài)；試劑盒法檢測大鼠血清肝功能、血脂以及肝臟氧化指標(biāo)水平；實時熒光定量PCR（qRT-PCR）法測定大鼠肝組織炎性因子基因表達(dá)水平； Western blotting法測定大鼠肝組織脂質(zhì)代謝相關(guān)蛋白水平；非靶向代謝組學(xué)分析大鼠肝組織代謝物譜。結(jié)果 與模型組比較，HQCF組血清三酰甘油（TG）、總膽固醇（ TC）、低密度脂蛋白膽固醇（LDL-C）、天冬氨酸氨基轉(zhuǎn)移酶（AST）、丙氨酸氨基轉(zhuǎn)移酶（ ALT）水平顯著下降（P＜0.01）；頸動脈纖維斑塊與鈣化灶生成明顯減少，肝臟組織脂肪變性明顯改善；肝組織中超氧化物歧化酶（SOD）活力顯著上調(diào)、丙二醛（MDA）含量顯著下調(diào)（P＜0.01），腫瘤壞死因子（TNF）-α、白細(xì)胞介素（IL）-6和IL-1β基因表達(dá)水平顯著下調(diào)（P＜0.01），脂肪酸合成酶（FAS）、膽固醇調(diào)節(jié)元件結(jié)合蛋白-1c（SREBP-1c）、前蛋白轉(zhuǎn)化酶枯草溶菌素9（PCSK9）蛋白表達(dá)水平顯著下調(diào)且過氧化物酶體增殖物激活受體γ（PPARγ）蛋白表達(dá)水平顯著上調(diào)（P＜0.01）；肝臟非靶向代謝共鑒定出30個差異代謝物，主要富集于初級膽汁酸生物合成、鞘脂代謝、色氨酸代謝等代謝途徑。結(jié)論 HQCF改善CAS大鼠血脂紊亂的作用機(jī)制與調(diào)節(jié)肝臟組織代謝物水平，從而改善肝臟脂質(zhì)代謝相關(guān)。

Objective To investigate the effect of Huangqi Chifeng Tang (HQCF) on hepatic lipid metabolism in rats with carotid atherosclerosis (CAS) based on metabolomics. Methods SD rats were randomly divided into five groups: sham operation group, model group, atorvastatin calcium tablet (Ato, 1.8 mg·kg^-1) group and HQCF low and high dose (1.53, 3.06 g·kg^-1) groups. The rat CAS model was established by arterial clamp surgery combined with high-fat diet feeding. Rats in the sham operation group only underwent carotid artery separation without using vascular clamps and were fed with basic feed. The modeling period lasted for 12 weeks. After the modeling was completed, intragastric administration was given once a day for 28 d. HE staining was used to evaluate the pathological morphology of the carotid arteries and livers of the rats. The levels of liver function, blood lipids and liver oxidative indicators in rat serum were detected by kit method. The expression levels of inflammatory factor genes in rat liver tissues were determined by real-time fluorescence quantitative PCR (qRT-PCR). The levels of lipid metabolism-related proteins in rat liver tissues were determined by Western blotting. Non-targeted metabolomics was used to analyze the metabolite profiles of rat liver tissues. Results Compared with the model group, the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the serum of the HQCF groups were significantly decreased (P < 0.01); The formation of carotid artery fibrous plaques and calcification foci was significantly reduced, and the fatty degeneration of liver tissue was significantly improved; the activity of superoxide dismutase (SOD) in liver tissue was significantly increased, and the content of malondialdehyde (MDA) was significantly decreased (P < 0.01); The expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β genes were significantly decreased (P < 0.01), and the expression levels of fatty acid synthase (FAS), sterol regulatory element-binding protein-1c (SREBP-1c), and proprotein convertase subtilisin/kexin type 9 (PCSK9) proteins were significantly decreased, while the expression level of peroxisome proliferator-activated receptor γ (PPARγ) protein was significantly increased (P < 0.01); A total of 30 differential metabolites were identified in the liver tissues of rats by non-targeted metabolomics, mainly enriched in primary bile acid biosynthesis, sphingolipid metabolism, tryptophan metabolism and other metabolic pathways. Conclusion The mechanism by which HQCF improves lipid disorders in CAS rats is related to the regulation of liver tissue metabolite levels, thereby improving liver lipid metabolism.

R285.5

黑龍江省自然科學(xué)基金項目（PL2024H239）