Περίληψη:
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-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Xbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, 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, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Nasiri-Ansari, N.
Nikolopoulou, C.
Papoutsi, K.
Kyrou, I.
Mantzoros, C.S.
Kyriakopoulos, G.
Chatzigeorgiou, A.
Kalotychou, V.
Randeva, M.S.
Chatha, K.
Kontzoglou, K.
Kaltsas, G.
Papavassiliou, A.G.
Randeva, H.S.
Kassi, E.
Λέξεις-κλειδιά:
acetyl coenzyme A carboxylase; activating transcription factor 4; activating transcription factor 6; acyl coenzyme A desaturase 1; amp activated protein kinase subunit alpha 1; amp activated protein kinase subunit alpha 2; beclin 1; CCAAT enhancer binding protein; egf like module containing mucin like hormone receptor like 1; empagliflozin; fatty acid synthase; glucose regulated protein 78; glucose regulated protein 94; hydroxymethylglutaryl coenzyme A reductase kinase; initiation factor 2alpha; interleukin 6; mammalian target of rapamycin; messenger RNA; microtubule associated protein 1; monocyte chemotactic protein 1; peroxisome proliferator activated receptor gamma; phosphoenolpyruvate carboxykinase (GTP); protein Bax; protein bcl 2; protein IRE1; sodium glucose cotransporter 1; sodium glucose cotransporter 2; sterol regulatory element binding protein 1; tumor necrosis factor; unclassified drug; X box binding protein 1; apolipoprotein E; benzhydryl derivative; empagliflozin; glucoside, animal experiment; animal model; animal tissue; apoptosis; Article; autophagy (cellular); controlled study; endoplasmic reticulum stress; histology; lipid diet; liver tissue; male; morphometry; mouse; mRNA expression level; nonalcoholic fatty liver; nonhuman; polyacrylamide gel electrophoresis; real time polymerase chain reaction; Western blotting; administration and dosage; adverse event; animal; autophagy; C57BL mouse; drug effect; gene expression regulation; genetics; immunoblotting; knockout mouse; lipogenesis; liver; metabolism; nonalcoholic fatty liver; pathology; pharmacology; reverse transcription polymerase chain reaction, Animals; Apolipoproteins E; Apoptosis; Autophagy; Benzhydryl Compounds; Diet, High-Fat; Endoplasmic Reticulum Stress; Gene Expression Regulation; Glucosides; Immunoblotting; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Reverse Transcriptase Polymerase Chain Reaction; Sodium-Glucose Transporter 2 Inhibitors
