Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway.
Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway.
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达帕利嗪通过AMPK-mTOR途径恢复自噬，从而减轻肝脏脂肪变性。
DOI：
10.3389/fphar.2021.589273
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发表时间：
2021
影响因子：
5.6
通讯作者：
Cheng Y
中科院分区：
文献类型：
--
作者：
Li L;Li Q;Huang W;Han Y;Tan H;An M;Xiang Q;Zhou R;Yang L;Cheng Y
钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂达格列净是一种新批准的口服降糖药，其来源于天然产物根皮苷，可有效降低血糖。近年来临床研究发现达格列净对非酒精性脂肪性肝病（NAFLD）有一定的治疗作用，但具体机制尚待进一步探讨。本研究旨在研究达格列净在体内外减轻肝细胞脂肪变性的潜在机制。采用高脂饲料喂养自发性2型糖尿病大鼠，用软脂酸（PA）诱导人正常肝LO 2细胞和人肝癌HepG 2细胞发生肝细胞脂肪变性。达格列净在体外和体内均可减轻肝脏脂质积聚。在Zucker糖尿病肥胖（ZDF）大鼠中，达格列净通过促进乙酰辅酶A羧化酶1（ACC 1）磷酸化和上调脂质β-氧化酶酰基辅酶A氧化酶1（ACOX 1）来减少肝脏脂质蓄积。此外，达格列净增加了自噬相关标志物LC 3B和Beclin 1的表达，同时降低了p62水平。在PA刺激的LO 2细胞和HepG 2细胞中观察到类似的作用。达格列净治疗还可以显著激活ZDF大鼠和PA刺激的LO 2细胞和HepG 2细胞中的AMPK并降低mTOR的磷酸化。我们证明，达格列净通过减少脂肪生成酶，同时诱导脂肪酸氧化酶和自噬来改善肝脂肪变性，这可能与AMPK激活有关。此外，我们的研究结果表明，达格列净通过AMPK-mTOR途径诱导自噬。这些发现揭示了达格列净治疗NAFLD的新的临床应用和作用机制。
As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo. We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo. In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid β-oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.
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DOI：
10.1073/pnas.1606022113
发表时间：
2016-06-14
影响因子：
11.1
作者：
Madiraju, Anila K.;Alves, Tiago;Shulman, Gerald I.
通讯作者：
Shulman, Gerald I.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
3.9
作者：
Brownsey, RW;Zhande, R;Boone, AN
通讯作者：
Boone, AN
影响因子：
--
作者：
Li, Yongmei;Zhang, Yuan;Lin, Laixiang
通讯作者：
Lin, Laixiang
DOI：
10.1007/s00018-018-2860-6
发表时间：
2018-09
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Ipsen DH;Lykkesfeldt J;Tveden-Nyborg P
通讯作者：
Tveden-Nyborg P