Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress

Petito-da-Silva, Tamiris Ingrid; Souza-Mello, Vanessa; Barbosa-da-Silva, Sandra

doi:10.1016/j.mce.2019.110539

Cited by 52 publications

(78 citation statements)

References 66 publications

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“…Empagliflozin, a new SGLT2i drug, has been shown in many studies to reduce body weight, improve fat distribution, promote lipophagy, and improve islet resistance in patients with type 2 diabetes. 30,31 Therefore, the mechanism of action of the SGLT2i empagliflozin in DN has been suggested to be related to the AdipoR1/p-AMPK/p-ACC pathway.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Zhang¹,

Ni²,

Zha³

et al. 2021

DMSO

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Background: Abnormal lipid deposition in the progress of diabetic nephropathy (DN) plays an important role in a number of studies that have shown that SGLT2 inhibitor (SGLT2i) empagliflozin plays an important role in lipid metabolism, but its mechanism is still unclear. Methods: We aimed to explore the effect of empagliflozin on lipid levels in kidney cancer patients with DN and postoperative patients without DN kidney carcinoma; the patients with DN showed ectopic lipid deposition. In type 2 diabetes model mice induced by streptozotocin (STZ) and a high-fat diet, combined AMPK plus empagliflozin or empagliflozin inhibitor plus compound C was applied, followed by analyses of the blood, urine and kidney indexes to observe the correlation between SGLT2i and AMPK and lipid metabolism in diabetic kidney disease. We determined whether DN in patients with renal tubular atrophy involved lipid metabolism. Results: In clinical specimens, the adiponectin receptor AdipoR1 was reduced, and the phosphorylation acetyl-CoA carboxylase (p-ACC) was increased. In vitro and in vivo pathological immunofluorescence and Western blotting confirmed that, under the condition of high glucose, malpighian tubules displayed ectopic lipid deposition and expressed related lipid parameters accompanied by fibrosis. Empagliflozin intervention reduced lipid deposition fibrosis and renal tubular atrophy, and the addition of compound C promoted disease progression. Moreover, siAdipoR1 transfection proved that AdipoR1 affected P-AMPK and then p-ACC affected lipid metabolism in renal tubular cells. Conclusion: According to the above experimental results, empagliflozin could reduce lipid metabolism of DN through AdipoR1/P-AMPK/P-ACC pathway and delay DN progress.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Zhang¹,

Ni²,

Zha³

et al. 2021

DMSO

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“…Thus, Empagli ozin can help in the early treatment of non-alcoholic fatty liver disease in T2D (17). A study by Sattar et al showed that Empagli ozin reduces aminotransferases in people with type 2 diabetes, which is potentially compatible with reduced liver fat, especially when ALT aminotransferase levels are high (12). According to a study by Gancheva et al (18), Empagli ozin effectively controls HCL in T2D patients and increases serum adiponectin with bene cial effects on hepatocyte integrity.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 90% of weight loss with Empagli ozin is due to the reduction of adipose mass in the visceral adipose tissue of the abdomen and subcutaneous tissue, which results in a very high probability of recovery of liver fat with Empagli ozin (9). Empagli ozin inhibits the progression of NAFLD by reducing the expression of genes involved in hepatic lipogenesis (10). While many reports are suggesting the bene cial effects of the Empagli ozin in non-alcoholic fatty liver disease and type 2 diabetes in mice models (11,12); only a few research studies are conducted as clinical trials to investigate its effect in NAFLD.…”

Section: Introductionmentioning

confidence: 99%

“…Empagli ozin inhibits the progression of NAFLD by reducing the expression of genes involved in hepatic lipogenesis (10). While many reports are suggesting the bene cial effects of the Empagli ozin in non-alcoholic fatty liver disease and type 2 diabetes in mice models (11,12); only a few research studies are conducted as clinical trials to investigate its effect in NAFLD. So, we aimed to provide a meta-analysis to combine these studies' results.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Empagliflozin on Liver Function in type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Trials

Roostaei

2020

Preprint

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Background Many reports are indicating the blood sugar-lowering potential of Empagliflozin in type 2 diabetes mellitus and its anti-lipogenesis effects in the liver, as studied in mice models; while few clinical trials have evaluated its effect on liver fat content and liver function. Objectives This study aimed to evaluate the effect of Empagliflozin on the treatment of non‐alcoholic fatty liver disease in type 2 diabetes mellitus patients.Search methods Scopus, Cochran Library, PubMed, and Web of Science databases were searched from 1990 to 2020 together with reference checking and citation searching to identify additional studies. Selection criteria Inclusion criteria for studies were the evaluation of patients with non‐alcoholic fatty liver disease and type 2 diabetes being treated with Empagliflozin for 24 weeks. Our interest outcomes were Liver fat, ALT, and AST. Data analysis Random effect size model was used for pooling data to calculate mean differences in RevMan Version 5.3. I2 was used to evaluate heterogeneity. Results Three clinical trial studies were included with 2344 patients. In pooled ALT ‎mean difference evaluation within 24 weeks of studies, there was a significant ‎difference between subjects receiving Empagliflozin versus controls (MD=-6.6 ‎CI95%(-10.27 to -3.73; P=0.06; I2=99%). ‎ In case of AST (MD=-9.06 CI95% (-20.45 to 2.34; P=0.12; I2=98%) and Liver fat (MD=-4.46 CI95% (-10.06 to 0.77; P=0.09; I2=98%), ‎there was not any significant difference between subjects receiving Empagliflozin ‎versus controls. Conclusion While Empagliflozin seems to be effective in lowering ALT levels; further studies are needed to confirm its efficacy in lowering liver fat.

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“…Aim of this study was to investigate systemic and cardiac tissue specific effects of empagliflozin treatment that are independent on known pleiotropic effects like reduction in body weight, change in body composition and improved hyperinsulinemia of long-term therapy [12][13][14] . To do so, we studied cardiac effects of short-term empagliflozin treatment in leptin-receptor dysfunctional (db/db) mice, a model for type II diabetes and diabetic cardiomyopathy 15 .…”

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confidence: 99%

Cardioprotective effects of short-term empagliflozin treatment in db/db mice

Radlinger¹,

Hornsteiner²,

Folie³

et al. 2020

Sci Rep

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Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.

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Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress

Cited by 52 publications

References 66 publications

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Effect of Empagliflozin on Liver Function in type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Trials

Cardioprotective effects of short-term empagliflozin treatment in db/db mice

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