PMID- 33551821
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210210
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 11
DP  - 2020
TI  - Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy 
      Pathway in vivo and in vitro.
PG  - 622153
LID - 10.3389/fphar.2020.622153 [doi]
LID - 622153
AB  - 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.
CI  - Copyright (c) 2021 Li, Fang, Xu, Liu, Li, Xue, Yu, Sun and Chen.
FAU - Li, Ting
AU  - Li T
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Fang, Ting
AU  - Fang T
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Xu, Linxin
AU  - Xu L
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Liu, Xiangyang
AU  - Liu X
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Li, Xiaoyu
AU  - Li X
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Xue, Mei
AU  - Xue M
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Yu, Xiaochen
AU  - Yu X
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Sun, Bei
AU  - Sun B
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
FAU - Chen, Liming
AU  - Chen L
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of 
      Endocrinology, Tianjin Medical University, Tianjin, China.
LA  - eng
PT  - Journal Article
DEP - 20210120
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC7854384
OTO - NOTNLM
OT  - autophagy
OT  - diabetes
OT  - empagliflozin
OT  - lipid accumulation
OT  - metabolic associated fatty liver disease
OT  - ten-eleven translocation 2
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/02/09 06:00
MHDA- 2021/02/09 06:01
PMCR- 2021/01/20
CRDT- 2021/02/08 05:35
PHST- 2020/10/27 00:00 [received]
PHST- 2020/12/14 00:00 [accepted]
PHST- 2021/02/08 05:35 [entrez]
PHST- 2021/02/09 06:00 [pubmed]
PHST- 2021/02/09 06:01 [medline]
PHST- 2021/01/20 00:00 [pmc-release]
AID - 622153 [pii]
AID - 10.3389/fphar.2020.622153 [doi]
PST - epublish
SO  - Front Pharmacol. 2021 Jan 20;11:622153. doi: 10.3389/fphar.2020.622153. 
      eCollection 2020.