Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway

Abstract

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.

Synthesis and Spectroscopic Characterization of Dapagliflozin/Zn (II), Cr (III) and Se (IV) Novel Complexes That Ameliorate Hepatic Damage, Hyperglycemia and Oxidative Injury Induced by Streptozotocin-Induced Diabetic Male Rats and Their Antibacterial Activity

“…Liuran et al [16] demonstrated that Dapg ameliorates hepatic steatosis by reducing lipogenic enzymes while inducing autophagy via the AMPK-mTOR pathway and thus improves hepatic functions and reduces hepatic lipid accumulation.…”

Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress

“…To further explore the effect of empagliflozin on hepatocytes, we used the HepG2 hepatocytes cell line, which was used to study SGLT-2 inhibitors [ 14 , 15 ]. The viability of HepG2 cells treated with empagliflozin was measured.…”

“…Similar results were obtained previously by other groups for the HepG2 cell line using other SGLT-2 inhibitors. Dapagliflozin ameliorated hepatic steatosis in Zucker diabetic fatty (ZDF) rats and palmitic acid-stimulated LO2 cells and HepG2 cells [ 14 ], while canagliflozin showed similar effects in a mouse model of diabetes and NASH-related hepatocellular carcinoma [ 41 ], leading the authors to suggest the use of dapagliflozin in the treatment of NASH or NAFLD [ 14 , 41 ]. Interestingly, in higher concentrations, (10 µM) canagliflozin also protected against liver carcinogenesis [ 41 , 42 ].…”

“…Glucose utilization in isolated epididymal adipose tissue was measured by incorporation of 14 C-U glucose into adipose tissue lipids. Glucose oxidation was determined in isolated diaphragmatic muscle by measuring the incorporation of 14 C-U glucose into CO 2 .…”

“…Palmitic acid utilization in myocardium was determined ex vivo by measuring 14 Cpalmitic acid oxidation to CO 2 . The removed left ventricle was immediately sliced and incubated for 2 h in 5 mL of Krebs-Ringer bicarbonate buffer, pH 7.4.…”