背景:代谢综合征(MetS),以肥胖为特征,高血糖症,血脂水平异常,是许多心血管疾病的病理基础。瓜楼-谢白-半夏汤(GT)最早是在《金殿要略》中描述的,中国最早的中医杂病诊疗专著。根据中医戒律,基于它激活阳以释放停滞的能力,激活气以减少抑郁,去痰,扩大胸部,GT已被用于治疗心血管疾病超过2,000年。然而,其治疗机制的分子基础尚不清楚.
目的:本研究的目的是鉴定由GT差异调节的与脂质和葡萄糖相关的肝脏基因,并评估GT对肠道菌群组成的影响,在高脂饮食(HFD)诱导的MetS小鼠中。
方法:ApoE-/-小鼠用HFD喂养24周,有或没有同时补充GT,诱导MetS。在研究结束时,体重,内脏脂肪重量,血脂水平,测量胰岛素敏感性,组织病理学染色用于评估肝骨病和肠屏障的完整性。肝脏转录组学用于分析肝脏中差异表达的基因和相关调节途径的预测。通过RT-qPCR和蛋白质印迹法检测肝脂/糖代谢相关基因和蛋白。通过16SrRNA基因测序确定肠道微生物组成。
结果:GT给药减少了与MetS相关的肝脏脂肪变性和体重增加,促进胰岛素敏感性和脂质代谢,并通过降低g_Lachnoshispileae_NK4A136_组的相对丰度和增加g_Alistipes的相对丰度来有益地调节肠道微生物群组成。肝脏转录组学显示,GT调节与脂质和葡萄糖代谢相关的基因的表达(Pparγ,Igf1,Gpnmb,和Trem2)以及编码趋化因子/趋化因子受体的基因(例如Cxcl9和Cx3cr1)。重要的,Ccr2,Ccl4,Ccr1和Cx3cr1与g_Lachnospiraceae_NK4A136_组呈正相关,在Cxcl9,Ccr2,Ccl4和Cx3cr1和g_脱硫弧菌之间。GT处理下调SCD1和CX3CR1的蛋白表达,上调PCK1蛋白表达。
结论:补充GT通过改善肝脏脂质和葡萄糖代谢减轻HFD诱导的小鼠MetS。GT的抗代谢综合征作用可能与肠-肝轴的调节有关。
BACKGROUND: Metabolic syndrome (MetS), characterized by obesity, hyperglycemia, and abnormal blood lipid levels, is the pathological basis of many cardiovascular diseases. Gualou-Xiebai-Banxia-Tang decoction (GT) was first described in the Synopsis of the Golden Chamber, the earliest traditional Chinese medicine (
TCM) monograph on diagnosis and treatment of miscellaneous diseases in China. According to
TCM precepts, based on its ability to activate yang to release stagnation, activate qi to reduce depression, remove phlegm, and broaden the chest, GT has been used for more than 2,000 years to treat cardiovascular ailments. However, the molecular bases of its therapeutic mechanisms remain unclear.
OBJECTIVE: The aim of this study was to identify lipid- and glucose-related hepatic genes differentially regulated by GT, and to assess GT impact on gut microbiota composition, in mice with high-fat diet (HFD)-induced MetS.
METHODS: ApoE-/- mice were fed with an HFD for 24 weeks, with or without concurrent GT supplementation, to induce MetS. At the study\'s end, body weight, visceral fat weight, blood lipid levels, and insulin sensitivity were measured, and histopathological staining was used to evaluate hepatosteatosis and intestinal barrier integrity. Liver transcriptomics was used for analysis of differentially expressed genes in liver and prediction of relevant regulatory pathways. Hepatic lipid/glucose metabolism-related genes and proteins were detected by RT-qPCR and western blotting. Gut microbial composition was determined by 16S rRNA gene sequencing.
RESULTS: GT administration reduced MetS-related liver steatosis and weight gain, promoted insulin sensitivity and lipid metabolism, and beneficially modulated gut microbiota composition by decreasing the relative abundance of g_Lachnospiraceae_NK4A136_group and increasing the relative abundance of g_Alistipes. Liver transcriptomics revealed that GT regulated the expression of genes related to lipid and glucose metabolism (Pparγ, Igf1, Gpnmb, and Trem2) and of genes encoding chemokines/chemokine receptors (e.g. Cxcl9 and Cx3cr1). Significant, positive correlations were found for Ccr2, Ccl4, Ccr1, and Cx3cr1 and the g_Lachnospiraceae_NK4A136_group, and between Cxcl9, Ccr2, Ccl4, and Cx3cr1 and g_Desulfovibrio. GT treatment downregulated the protein expressions of SCD1 and CX3CR1 and upregulated the expression of PCK1 protein.
CONCLUSIONS: GT supplementation alleviates HFD-induced MetS in mice by improving hepatic lipid and glucose metabolism. The anti-metabolic syndrome effects of GT may be related to the regulation of the gut-liver axis.