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-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, 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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide [1,2]
Empagliflozin administration had no significant effect on body weight as both high-fat diet (HFD)-fed apolipoprotein E (ApoE)(-/-) mice groups significantly increased their body weight at the end of the five-week intervention compared to baseline (18.7% and 17.9% increase in body weight in the Empa and the control group, respectively)
Empagliflozin treatment resulted in significantly reduced fasting glucose, total cholesterol, and triglyceride serum levels at the end of the five-week intervention compared to baseline
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide [1,2]. Higher prevalence of type 2 diabetes (DMT2) has been documented among NAFLD and NASH patients, while NAFLD markedly increases the risk of developing DMT2 [3]. NAFLD and DMT2 share common pathophysiologic features, with insulin resistance playing a key pathogenic role [4]. Anti-diabetic drugs (e.g., metformin, thiazolidinediones and GLP-1 analogues) have been studied as potential treatments against NAFLD/NASH development and progression [5,6]. Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) represent a new class of anti-diabetic drugs which act mainly through increasing urinary glucose excretion and, improve glucose control independently of insulin secretion [7]. In addition to glucose reduction, SGLT-2i has been shown to exert certain beneficial cardio-metabolic effects, including weight reduction and cardiovascular disease (CVD) protection [8,9,10]
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