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Purpose: Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating cardiovascular and renal disorders, its impacts and mechanisms on NAFLD are poorly understood. This research aimed to examine the metabolic regulatory mechanism through which empagliflozin protects against NAFLD.Methods: Equal grouping of twenty-seven male C57BL/6J mice into those fed a normal diet (NCD), those fed a high-fat diet (HFD), and those fed an HFD with empagliflozin (Empa) was approached. HE, oil red O staining, and Masson staining were utilized for evaluating the pathological damage to the liver and the mice's liver and body weights. Lipids, blood glucose, and inflammation index were compared across the three groups. Liquid chromatography/mass spectrometry (LC-MS) has been employed for identifying liver metabolomics.Results: The findings suggested that empagliflozin mitigated the inflammatory and oxidative stress response associated with the buildup of lipids caused by HFD. Differentially expressed metabolites (DEMs) were identified by metabonomics analysis as present in both the HFD/NCD and Empa/HFD groups. These DEMs were primarily found in lipids and organic acids like lysophosphatidylcholine (lysoPC), lecithin (PC), triglyceride (TG), palmitic acid, and L-isoleucine. Among the enriched pathways that were shown to be important were those involved in the metabolism of histidine, arachidonic acid, the control of lipolysis in adipocytes, and insulin resistance. There was a strong correlation between inflammation and oxidative stress in most of the metabolites. The inflammation and oxidative stress unbalance were ameliorated by empagliflozin.Conclusion: NAFLD mice model showed considerable improvement in metabolic abnormalities and liver protection after treatment with empagliflozin. The process may include the overexpression of L-isoleucine and the downregulation of lysoPC, PC, TG, and palmitic acid to reduce liver harm caused by lipotoxicity. [ABSTRACT FROM AUTHOR]

With an increasing prevalence of obesity related kidney disease, exploring the mechanisms of therapeutic method is of critical importance. Empagliflozin is a new antidiabetic agent with broad clinical application prospect in cardiovascular and renal diseases. However, a metabonomics-based renoprotective mechanism of empagliflozin in obesity remains unclear. Our results showed that empagliflozin significantly alleviated the deposition of lipid droplet, glomerular and tubular injury. The innovation lied in detection of empagliflozin-targeted differential metabolites in kidneys. Compared with normal control mice, obese mice showed higher levels of All-trans-heptaprenyl diphosphate, Biliverdin, Galabiose, Galabiosylceramide (d18:1/16:0), Inosine, Methylisocitric acid, Uric acid, Xanthosine, O-glutarylcarnitine, PG(20:3(8Z,11Z,14Z)/0:0), PG(20:4(5Z,8Z,11Z,14Z)/0:0), PE(O-16:0/0:0), PG(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/0:0), and lower level of Adenosine. Empagliflozin regulated these metabolites in the opposite direction. Associated metabolic pathways were Phospholipids metabolism, Purine metabolism, and Biliverdin metabolism. Most of metabolites were associated with inflammatory response and oxidative stress. Empagliflozin improved the oxidative stress and inflammation imbalance. Our study revealed the metabonomics-based renoprotective mechanism of empagliflozin in obese mice for the first time. Empagliflozin may be a promising tool to delay the progression of obesity-related kidney disease. • A metabonomics-based renoprotective mechanism of empagliflozin in obesity remains unclear. • For the first time, metabolites, such as Adenosine, Uric acid, and Biliverdin were identified. • The molecular pathways were related to Phospholipids, Biliverdin and Purine metabolism. • Empagliflozin improved the oxidative stress and inflammation imbalance. • New insights into the renoprotective mechanisms of empagliflozin in targets for therapy. [ABSTRACT FROM AUTHOR]