Gegen Qinlian Decoction Coordinately Regulates PPARγ and PPARα to Improve Glucose and Lipid Homeostasis in Diabetic Rats and Insulin Resistance 3T3-L1 Adipocytes
Gegen Qinlian Decoction Coordinately Regulates PPARγ and PPARα to Improve Glucose and Lipid Homeostasis in Diabetic Rats and Insulin Resistance 3T3-L1 Adipocytes
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葛根芹连汤协同调节PPARγ和PPARα改善糖尿病大鼠糖脂稳态及胰岛素抵抗3T3-L1脂肪细胞
DOI：
10.3389/fphar.2020.00811
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发表时间：
2020-06-11
影响因子：
5.6
通讯作者：
Chen, Chen
中科院分区：
文献类型：
--
作者：
Tu, Jun;Zhu, Shuilan;Chen, Chen
葛根芩连汤（GQD）是一种有据可查的中药方剂，据报道在临床实践中具有令人信服的抗糖尿病作用。然而，GQD 的确切抗糖尿病机制仍不清楚。在这项研究中，GQD 的抗高血糖和/或降脂作用在高脂饮食和低剂量链脲佐菌素诱导的糖尿病 Sprague-Dawley 大鼠和胰岛素抵抗 (IR)-3T3-L1 脂肪细胞中得到证实。 GQD 治疗增加了脂肪细胞中 PPAR γ 和 PPAR α 的表达和活性水平，这在体内和体外转录影响了葡萄糖和脂质代谢基因的整体。结果清楚地表明，GQD 治疗干预了由脂肪细胞 PPAR γ 和 PPAR α 的同时下游效应控制的多种途径，从而影响两个相反的脂质途径：脂肪酸氧化和脂质合成。拮抗剂GW9662降低Pparγ及靶基因Adpn和Glut4的mRNA表达，GW6471降低Pparα及靶基因Cpt-1α、Lpl、Mcad、Lcad、Acox1等的mRNA表达。核定位和活性实验表明，更多的PPARγ和PPARα穿梭入核，增强其与靶基因的结合活性。 GQD 通过翻译后修饰降低 ERK1/2 和/或 CDK5 的磷酸化水平，从而提高 IR-3T3-L1 脂肪细胞中的 PPAR γ 和 PPAR α 活性。 GQD 治疗下 p-p38MAPK 和 SIRT1 的增加可能归因于部分降低 PPAR γ 脂肪生成活性和/或激活 PPAR α 活性。与罗格列酮治疗组相比，GQD 升高了 Cpt-1 α 表达，降低了糖尿病生物标志物 Fabp4 表达，从而产生了令人鼓舞的血脂谱，甘油三酯降低部分是由于对脂肪细胞 PPAR γ 和 PPAR α 活性上调的综合作用。这些结果表明，GQD 通过干预多种 PPAR γ 和 PPAR α 上下游信号转导级联来改善糖尿病，与 PPAR γ 全激动剂罗格列酮相比，联合优化靶基因谱的表达，促进脂肪酸氧化并加速葡萄糖的摄取和利用，而不刺激 PPAR α 活性。因此，GQD 显示出抗糖尿病/或抗高血糖作用，部分是通过调节脂肪细胞 PPAR α 和 PPAR γ 信号系统来维持平衡的葡萄糖和脂质代谢。该研究为GQD作为PPARα/γ双重激动剂的抗糖尿病作用提供了新的见解，以加速其临床应用。
Gegen Qinlian Decoction (GQD), a well-documented traditional Chinese Medicine (TCM) formula, was reported with convincing anti-diabetic effects in clinical practice. However, the precise antidiabetic mechanism of GQD remains unknown. In this study, the anti-hyperglycemic and/or lipid lowering effects of GQD were demonstrated in high-fat diet with a low dose of streptozotocin induced diabetic Sprague-Dawley rats and insulin resistance (IR)-3T3-L1 adipocytes. GQD treatment increased expression and activity levels of both PPAR gamma and PPAR alpha in adipocytes, which transcriptionally affected an ensemble of glucose and lipid metabolic genesin vivoandin vitro. The results clearly indicated that GQD treatment intervened with multiple pathways controlled by concomitantly downstream effects of adipocytic PPAR gamma and PPAR alpha, to influence two opposite lipid pathways: fatty acid oxidation and lipid synthesis. Antagonist GW9662 decreased the mRNA expression ofPpar gamma and target genesAdpnandGlut4whereas GW6471 decreased the mRNA expression ofPpar alpha and target genesCpt-1 alpha,Lpl,Mcad,Lcad,Acox1, etc. Nuclear location and activity experiments showed that more PPAR gamma and PPAR alpha shuttled into nuclear to increase its binding activities with target genes. GQD decreased the phosphorylation level of ERK1/2 and/or CDK5 to elevate PPAR gamma and PPAR alpha activities in IR-3T3-L1 adipocytes through post-translational modification. The increase in p-p38MAPK and SIRT1 under GQD treatment may be attributed to partially reduce PPAR gamma adipogenesis activity and/or activate PPAR alpha activity. Compared with the rosiglitazone-treated group, GQD elevatedCpt-1 alpha expression, decreased diabetic biomarkerFabp4expression, which produced an encouraging lipid profile with triglyceride decrease partially from combined effects on upregulated adipocytic PPAR gamma and PPAR alpha activities. These results suggested that GQD improved diabetes by intervening a diverse array of PPAR gamma and PPAR alpha upstream and downstream signaling transduction cascades, which jointly optimized the expression of target gene profiles to promote fatty acid oxidation and accelerate glucose uptake and utilization than PPAR gamma full agonist rosiglitazone without stimulating PPAR alpha activity. Thus, GQD showed anti-diabetic/or antihyperglycemic effects, partially through regulating adipocytic PPAR alpha and PPAR gamma signaling systems to maintaining balanced glucose and lipid metabolisms. This study provides a new insight into the anti-diabetic effect of GQD as a PPAR alpha/gamma dual agonist to accelerate the clinical use.