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  3. Dapagliflozin attenuates steatosis in livers of high-fat diet-induced mice and oleic acid-treated L02 cells via regulating AMPK/mTOR pathway

Dapagliflozin attenuates steatosis in livers of high-fat diet-induced mice and oleic acid-treated L02 cells via regulating AMPK/mTOR pathway

  • Eur J Pharmacol. 2021 Sep 15;907:174304. doi: 10.1016/j.ejphar.2021.174304.
Jingyi Luo 1,  Pengbo Sun 2,  Yangyang Wang 2,  Yang Chen 1,  Yaoyun Niu 3,  Yipei Ding 1,  Naihan Xu 4,  Yaou Zhang 4,  Weidong Xie 5
Affiliations

Affiliations

  • 1 Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China; Department of Chemistry, Tsinghua University, Beijing, 100084, PR China.
  • 2 Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China; State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China; Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
  • 3 Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China; State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China.
  • 4 Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China; Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
  • 5 Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, PR China; Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China. Electronic address: xiewd@sz.tsinghua.edu.cn.
PMID: 34224699 DOI: 10.1016/j.ejphar.2021.174304
Abstract

Dapagliflozin (DAPA), a kind of sodium-glucose cotransporter 2(SGLT2) inhibitor is used to treat diabetes mellitus by inhibiting urine glucose reuptake. Recent clinical outcomes indicate that SGLT2 inhibitors may exert pharmacological activities against non-alcoholic fatty liver diseases. Nonetheless, the underlying molecular mechanisms are still poorly elucidated. In this study, we investigated the potential anti-fatty liver effects of DAPA in vivo and in vitro and assayed their underlying mechanisms. Male NIH (National Institutes of Health) mice were fed with a high-fat diet (HFD) and then treated with DAPA by gavage for 4 weeks. In the following experiments, L02 cells were treated with oleic acid (OA) and different concentrations of DAPA to assess lipid metabolism. Our results revealed that DAPA administration could remarkably suppress excessive fat accumulation in the liver tissues of HFD-fed mice and OA-treated L02 cells. Importantly, DAPA could downregulate the expression levels of proteins related to lipid synthesis and upregulate the expression levels of genes associated with fatty acid oxidation in vitro and in vivo. We also found that DAPA intervention could activate adenosine monophosphate-activated protein kinase (AMPK) phosphorylation but inhibit mammalian target of rapamycin (mTOR) phosphorylation in vitro and in vivo. AMPK activation might be mediated by increasing liver kinase B1 activity and decreasing ATP level. Furthermore, these ameliorative effects were completely eliminated by an AMPK Inhibitor, compound C. This study suggested that DAPA might remarkably ameliorate hepatic steatosis mediated through the AMPK/mTOR pathway and thus could be a potential drug candidate for the treatment of fatty liver diseases.

Keywords

AMPK; Dapagliflozin; Hepatic steatosis; NAFLD; mTOR.

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