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Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis
- Source :
- International Journal of Molecular Sciences, Vol 22, Iss 818, p 818 (2021), International Journal of Molecular Sciences, Volume 22, Issue 2
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Aims/hypothesis: SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. Methods: Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-&gamma<br />Pck-1, Mcp-1, Tnf-&alpha<br />Il-6, F4/80, Atf4, Elf2&alpha<br />Chop, Grp78, Grp94, &Chi<br />bp1, Ire1&alpha<br />Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2&alpha<br />EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. Results: Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1&alpha<br />Xbp1, Elf2&alpha<br />Atf4, Atf6, Chop, P62(Sqstm1) and Grp94<br />whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. Conclusion: These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
- Subjects :
- 0301 basic medicine
Apolipoprotein E
medicine.medical_specialty
autophagy
030209 endocrinology & metabolism
CHOP
Catalysis
Inorganic Chemistry
lcsh:Chemistry
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
NAFLD
Empagliflozin
medicine
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
PI3K/AKT/mTOR pathway
Triglyceride
Liver cell
Organic Chemistry
Fatty liver
Autophagy
SGLT-2 inhibitors
apoptosis
nutritional and metabolic diseases
General Medicine
medicine.disease
Computer Science Applications
030104 developmental biology
Endocrinology
chemistry
lcsh:Biology (General)
lcsh:QD1-999
inflammation
ER stress
Subjects
Details
- Language :
- English
- ISSN :
- 16616596 and 14220067
- Volume :
- 22
- Issue :
- 818
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....f4eb4d9f8e37a074cd9f6541c6971199