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Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro.

ABSTRACT: Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood. Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels. Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment. Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

SUBMITTER: Li T

PROVIDER: S-EPMC7854384 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro.

Li Ting T Fang Ting T Xu Linxin L Liu Xiangyang X Li Xiaoyu X Xue Mei M Yu Xiaochen X Sun Bei B Chen Liming L

Frontiers in pharmacology 20210120

Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood. Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrica ...[more]

PMID: 33551821

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Project description:Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

Dataset Information

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro.

Publications

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway <i>in vivo</i> and <i>in vitro</i>.

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